Melatonin is considered a promising antitumor agent, promoting apoptosis in tumor cells and contrasting it in normal cells. The basis for this selectivity is presumed to be the ability of melatonin to stimulate reactive oxygen species (ROS) production in tumor cells. Here we investigate the effect of melatonin on three types of human lymphocytes: normal blood lymphocytes, BL41 Burkitt lymphoma, and the cognate Epstein-Barr virus (EBV)-converted E2r. We found that melatonin promotes ROS production in all these cells. Melatonin protects BL41 from apoptosis in the same manner as normal lymphocytes, whereas E2r are unaffected. These results show that ROS production is not limited to tumor lymphocytes nor it is involved in apoptosis promotion; tha melatonin does not promote apoptosis in tumor lymphocytes, but EBV inhibits melatonin anti-apoptotic effects; and that the anti-apoptotic effect of melatonin does not depend on the well-known chemical antioxidant properties of melatonin.