Chronic diarrhea and colitis are common in patients positive for human immunodeficiency virus (HIV) under highly active antiretroviral treatment (HAART). This prospective double-blind study explores the effect of mesalamine vs. placebo in HIV-positive patients. Thirteen HIV-infected patients with noninfectious chronic diarrhea and > 250 CD4+ cells/mm³ were randomized to mesalamine (2.4 g/day; n = 9) or placebo (n = 4) for 6 weeks. Colonoscopy was performed at baseline and week 6, and biopsies were obtained to calculate the Biopsy Activity Index (BAI). Diarrhea was assessed at baseline and end of treatment using the Disease Activity Index (DAI). Patients and clinicians completed Patient Global Improvement index (PGI) and Clinical Global Improvement index (CGI) at weeks 2 and 6. Comparisons at week 6 were statistically significant between mesalamine and placebo groups for BAI (P = 0.03), DAI (P = 0.007), PGI (P = 0.008), and CGI (P = 0.008). Furthermore, major improvements were documented in the mesalamine group at week 6 compared to baseline for all variables, whereas the placebo group did not have any. Mesalamine was effective for treatment of chronic diarrhea and moderate nonspecific colitis in HIV patients.