Background Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with no effective cure. Resveratrol (RSV) is a polyphenol present in the grape. Its anti-tumor effects have been reported previously. We investigated antiproliferative effect of RSV on MPM cells and examined if this effect is through antioxidant system. Method Two different human MPM cells, epitheloid (NCI-H2452) and biphasic (MSTO-211H) MPM cells, are treated with RSV at different concentrations (5-250 μM) and different exposure times (24h, 48h, 72h) and then antiproliferative effects were determined by WST-1 assay. To figure out if this effect is through ROS production, intracellular ROS were measured by flow cytometry. Furthermore the expressions of antioxidant enzymes were evaluated by Western Blot analysis to explain the mechanism of this effect. Results RSV reduced the cell proliferation of both cell lines in a concentration dependent and exposure time- dependent manner compared to control. The ROS levels in the cells were elevated with RSV treatment. The expression of SOD2 increased significantly in biphasic MPM cells by RSV. But we could not find significant changes on SOD2 expression of epitheloid MPM cells with RSV treatment. Conclusion These results suggest that the treatment of MPM cells with RSV causes significant inhibition of cell proliferation and this effect is associated with increase of ROS production in the cells. The mechanism of this increased production can be explained with increased SOD2 expression in the cells.