Curcumin exhibits both cancer- preventive activity and growth inhibitory effects on several neoplastic cells including human colon cancer. Serotonin and its receptors have also been implicated in tumor development. This study investigated the effect of ritanserin, a selective serotonin 5HT_2A receptor antagonist, alone and in combination with curcumin on colorectal cancer cell lines. Results show that the expression of the serotonin 5HT_2A receptor is higher in tumor than in normal colorectal tissues. Ritanserin, reduced cell viability in a dose-dependent manner, and increased apoptosis in HT29, SW480 and SW742 colorectal cancer cell lines as analyzed by MTT and TUNEL assays, respectively. Moreover, combined with curcumin, ritanserin synergistically increased the number of hypodiploid cells and DNA fragmentation and decreased cell viability in all colorectal cancer cell lines. This study demonstrates that curcumin and ritanserin have a synergic anti- mitogenic and apoptotic effect on colorectal cancer cell lines. These results suggest a potential use of serotonin 5HT_2A receptor antagonist in co- treatment with curcumin in colon cancer therapy.