Inflammatory bowel disease has been linked to elevated T cells. Excessive production of reactive oxygen species and apoptosis are known to be accompanied by intestinal inflammation. This study was designed to investigate the effects of melatonin (MEL) and erythropoietin (EPO), which is a known anti-inflammatory and antiapoptotic agent, in dinitrobenzene sulfonic acid (DNBS)induced colitis in pinealectomized (Px) rats. In microscopically results, epithelial and goblet cell loss, absence of crypts, and increased colonic caspase-3 activity were observed in the DNBS group. Also, in flow cytometric analysis, the percentage of CD4+ T cells was highest in the DNBS group. Treatment with MEL or EPO had a curative effect on DNBS-induced colitis. The MEL+EPO groups showed significantly greater improvement when compared with the other treatment groups. Our results indicate that the combination of EPO and MEL may exert more beneficial effects than either agent used alone.