C-phycocyanin, which is a major biliprotein of the blue-green algae, has been shown to possess cyclooxygenase-2 inhibitory activity. We have studied the effect of phycocyanin on a rat histiocytic tumor line. AK-5 cells are induced into apoptotic death program when treated with phycocyanin, which involves the activation of caspase-3. Phycocyanin-mediated apoptotic death is induced through the generation of reactive oxygen radicals. Free radical scavengers inhibited phycocyanin-induced apoptotic death in AK-5 cells. Bcl-2, an inhibitor of apoptosis, is shown to regulate ROS generation. Bcl-2 gene-transfected AK-5 cells are resistant to phycocyanin-induced death. Overexpression of Bcl-2 inhibited the production of ROS in phycocyanin-treated AK-5 cells. Thus, our observations demonstrate phycocyanin-induced apoptotic death in AK-5 cells, which is inhibited by Bcl-2 expression through the regulation of free radical generation. Phycocyanin, a natural product, could therefore be a possible chemotherapeutic agent through its apoptotic activity against tumor cells.