The article presents a proteomics dataset focusing on the colon mucosa from patients with inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), as well as control subjects. The study aims to investigate the altered proteome composition in these conditions, which is hypothesized to be related to the gut microbiota changes observed in these patients. The dataset includes colon mucosal biopsies from 10 ulcerative colitis patients, 11 gastrointestinal healthy RA patients, and 10 controls. The biopsies were collected using sigmoidoscopy and analyzed using liquid chromatography mass spectrometry (LC-MS/MS) in a label-free manner to enable comparison between all samples. The proteomics data and search results have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with dataset identifiers PXD001608 for ulcerative colitis and control samples, and PXD003082 for RA samples. The study provides valuable insights into the proteome changes in IBD and RA, contributing to a better understanding of these inflammatory conditions.The article presents a proteomics dataset focusing on the colon mucosa from patients with inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), as well as control subjects. The study aims to investigate the altered proteome composition in these conditions, which is hypothesized to be related to the gut microbiota changes observed in these patients. The dataset includes colon mucosal biopsies from 10 ulcerative colitis patients, 11 gastrointestinal healthy RA patients, and 10 controls. The biopsies were collected using sigmoidoscopy and analyzed using liquid chromatography mass spectrometry (LC-MS/MS) in a label-free manner to enable comparison between all samples. The proteomics data and search results have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with dataset identifiers PXD001608 for ulcerative colitis and control samples, and PXD003082 for RA samples. The study provides valuable insights into the proteome changes in IBD and RA, contributing to a better understanding of these inflammatory conditions.