This study presents a proteomics dataset comparing the colon mucosa of inflammatory bowel disease (IBD) patients with ulcerative colitis (UC), gastrointestinal asymptomatic rheumatoid arthritis (RA) patients, and healthy controls. The dataset includes 10 UC patients, 11 RA patients, and 10 controls, with colon mucosa biopsies collected via sigmoidoscopy. All samples were processed in one batch, allowing for label-free comparison. The proteomics data, obtained using liquid chromatography mass spectrometry (LC-MS/MS), were deposited in the ProteomeXchange Consortium via the PRIDE partner repository with identifiers PXD001608 (UC and control samples) and PXD003082 (RA samples). A total of 6768 proteins were identified with a false discovery rate (FDR) <1%, representing the largest proteome dataset of the colon mucosa to date. The dataset provides insights into the proteome of the colon mucosa in RA patients, who are typically asymptomatic for gastrointestinal issues, and allows for further research on disease-related proteome effects and treatments. The data are publicly available for critical or extended analyses, and the study encourages collaborations for further statistical analysis. The dataset was obtained under ethical approval and with informed consent from all participants. The study highlights the importance of the colon mucosa as the main interface between the gut microbiota and the immune system, and the altered composition of the gut microbiota in both RA and IBD patients. The data are available for further research and analysis.This study presents a proteomics dataset comparing the colon mucosa of inflammatory bowel disease (IBD) patients with ulcerative colitis (UC), gastrointestinal asymptomatic rheumatoid arthritis (RA) patients, and healthy controls. The dataset includes 10 UC patients, 11 RA patients, and 10 controls, with colon mucosa biopsies collected via sigmoidoscopy. All samples were processed in one batch, allowing for label-free comparison. The proteomics data, obtained using liquid chromatography mass spectrometry (LC-MS/MS), were deposited in the ProteomeXchange Consortium via the PRIDE partner repository with identifiers PXD001608 (UC and control samples) and PXD003082 (RA samples). A total of 6768 proteins were identified with a false discovery rate (FDR) <1%, representing the largest proteome dataset of the colon mucosa to date. The dataset provides insights into the proteome of the colon mucosa in RA patients, who are typically asymptomatic for gastrointestinal issues, and allows for further research on disease-related proteome effects and treatments. The data are publicly available for critical or extended analyses, and the study encourages collaborations for further statistical analysis. The dataset was obtained under ethical approval and with informed consent from all participants. The study highlights the importance of the colon mucosa as the main interface between the gut microbiota and the immune system, and the altered composition of the gut microbiota in both RA and IBD patients. The data are available for further research and analysis.