Context: Obesity is a major global health problem associated with various adverse effects. Pharmacological interventions are often necessary for the management of obesity. Orlistat is an FDA-approved antiobesity drug which is a potent inhibitor of intestinal lipases. Objective: In the current study, orlistat was evaluated for its genotoxic potential in human lymphocyte cells in vitro and was compared with that of another antiobesity drug sibutramine, presently withdrawn from market due its undesirable health effects. Caffeine intake may be an additional burden in people using anorectic drugs, therefore, further work is needed to be carried out to evaluate the possible effects of caffeine on orlistat-induced DNA damage. Materials and methods: Human lymphocytes were exposed to orlistat (250, 500 and 1000 mu g/ml), sibutramine (250, 500 and 1000 mu g/ml) and caffeine (25, 50, 75, 100, 125 and 150 mu g/ml) to assess their genotoxicity by comet assay in vitro. In addition, lymphocytes were co-incubated with caffeine (50, 75 and 100 mu g/ml) and a single concentration of orlistat (250 mu g/ml). Results: Orlistat and sibutramine were genotoxic at all concentrations tested, sibutramine being more genotoxic. Caffeine was found to be genotoxic at concentrations 125 mu g/ml and above. Co-treatment of orlistat with non-genotoxic concentrations (50, 75 and 100 mu g/ml) of caffeine lead to a decrease in DNA damage. Discussion and conclusion: Orlistat can induce DNA damage in human lymphocytes in vitro and caffeine was found to reduce orlistat-induced genotoxicity.