Smoking significantly alters both innate and adaptive immune responses, with effects on innate responses disappearing after smoking cessation but persisting in adaptive responses through epigenetic memory. The study identified smoking, cytomegalovirus (CMV) latent infection, and body mass index (BMI) as major contributors to variability in cytokine secretion, comparable in magnitude to age, sex, and genetics. Smoking influences cytokine responses, with effects on innate responses linked to plasma levels of CEACAM6 and effects on adaptive responses associated with DNA methylation at signal trans-activators and metabolism regulators. These findings highlight the role of smoking in both short- and long-term immune regulation, with potential clinical implications for infection, cancer, and autoimmune diseases. The Milieu Intérieur project, which studied immune responses in a genetically homogeneous cohort, revealed that smoking affects cytokine secretion through both direct and epigenetic mechanisms. The study also identified genetic variants associated with cytokine responses and demonstrated that smoking interacts with genetic factors, particularly in BCG stimulation. Overall, the research underscores the complex interplay between environmental factors, genetics, and immune responses, emphasizing the need to consider these variables in immune-related disease risk assessment.Smoking significantly alters both innate and adaptive immune responses, with effects on innate responses disappearing after smoking cessation but persisting in adaptive responses through epigenetic memory. The study identified smoking, cytomegalovirus (CMV) latent infection, and body mass index (BMI) as major contributors to variability in cytokine secretion, comparable in magnitude to age, sex, and genetics. Smoking influences cytokine responses, with effects on innate responses linked to plasma levels of CEACAM6 and effects on adaptive responses associated with DNA methylation at signal trans-activators and metabolism regulators. These findings highlight the role of smoking in both short- and long-term immune regulation, with potential clinical implications for infection, cancer, and autoimmune diseases. The Milieu Intérieur project, which studied immune responses in a genetically homogeneous cohort, revealed that smoking affects cytokine secretion through both direct and epigenetic mechanisms. The study also identified genetic variants associated with cytokine responses and demonstrated that smoking interacts with genetic factors, particularly in BCG stimulation. Overall, the research underscores the complex interplay between environmental factors, genetics, and immune responses, emphasizing the need to consider these variables in immune-related disease risk assessment.