Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nrf2 is a transcription factor that regulates oxidative and xenobiotic stress responses and also represses inflammation. This study demonstrates that Nrf2 inhibits the transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β, in macrophages. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes and inhibits RNA Pol II recruitment. Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. These findings indicate that Nrf2 is the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. Nrf2 is essential for controlling inflammation, as its deficiency exacerbates inflammation in various murine models and causes autoimmune phenotypes in some strains. Nrf2 activation in myeloid cells alleviates inflammation, and NRF2 inducer Tecfidera has been approved for the treatment of multiple sclerosis. Nrf2's regulatory system is an attractive drug target due to its complex mechanism. Under unstressed conditions, Nrf2 is constitutively degraded through binding to Keap1, an E3 ubiquitin ligase adapter protein. In the presence of oxidative and xenobiotic stresses, Nrf2 degradation is stalled, leading to its accumulation and nuclear translocation. Nrf2 then forms a heterodimer with small Maf proteins and binds to the regulatory regions of target genes to upregulate their transcription. Small molecules have been found to disrupt Keap1-mediated degradation of Nrf2 and cause Nrf2 accumulation. However, the mechanism underlying Nrf2-mediated anti-inflammation has not been clarified in detail. Nrf2 upregulates numerous antioxidant genes, and elimination of reactive oxygen species (ROS) has been considered the molecular basis of Nrf2-mediated anti-inflammation. However, Nrf2 regulates the expression of macrophage-specific genes that are not categorized as anti-oxidative stress-response genes. These insights imply that Nrf2 may also act as an anti-inflammatory regulator in a ROS-independent manner. This study explored Nrf2 target genes in the inflammatory state using proinflammatory (M1-) activated and anti-inflammatory (M2-) activated macrophages. Microarray and Nrf2 ChIP-seq analyses revealed that Nrf2 binds to the proximity of the proinflammatory cytokine genes, including IL6 and IL1b, and inhibits lipopolysaccharide (LPS)-induced expression of these genes. This Nrf2-mediated transcriptional interference appears independent of ROS levels and independent of ARE. Nrf2 activation significantlyNrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nrf2 is a transcription factor that regulates oxidative and xenobiotic stress responses and also represses inflammation. This study demonstrates that Nrf2 inhibits the transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β, in macrophages. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes and inhibits RNA Pol II recruitment. Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. These findings indicate that Nrf2 is the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. Nrf2 is essential for controlling inflammation, as its deficiency exacerbates inflammation in various murine models and causes autoimmune phenotypes in some strains. Nrf2 activation in myeloid cells alleviates inflammation, and NRF2 inducer Tecfidera has been approved for the treatment of multiple sclerosis. Nrf2's regulatory system is an attractive drug target due to its complex mechanism. Under unstressed conditions, Nrf2 is constitutively degraded through binding to Keap1, an E3 ubiquitin ligase adapter protein. In the presence of oxidative and xenobiotic stresses, Nrf2 degradation is stalled, leading to its accumulation and nuclear translocation. Nrf2 then forms a heterodimer with small Maf proteins and binds to the regulatory regions of target genes to upregulate their transcription. Small molecules have been found to disrupt Keap1-mediated degradation of Nrf2 and cause Nrf2 accumulation. However, the mechanism underlying Nrf2-mediated anti-inflammation has not been clarified in detail. Nrf2 upregulates numerous antioxidant genes, and elimination of reactive oxygen species (ROS) has been considered the molecular basis of Nrf2-mediated anti-inflammation. However, Nrf2 regulates the expression of macrophage-specific genes that are not categorized as anti-oxidative stress-response genes. These insights imply that Nrf2 may also act as an anti-inflammatory regulator in a ROS-independent manner. This study explored Nrf2 target genes in the inflammatory state using proinflammatory (M1-) activated and anti-inflammatory (M2-) activated macrophages. Microarray and Nrf2 ChIP-seq analyses revealed that Nrf2 binds to the proximity of the proinflammatory cytokine genes, including IL6 and IL1b, and inhibits lipopolysaccharide (LPS)-induced expression of these genes. This Nrf2-mediated transcriptional interference appears independent of ROS levels and independent of ARE. Nrf2 activation significantly