The present study aims to investigate the anti-proliferative, apoptotic properties of prodigiosin, using a human oral squamous cell carcinoma HSC-2 cell line as a model system. HSC- 2 cells were cultured in the presence of prodigiosin at various concentrations (1–30µg/ml) for 48 h and the percentage of cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The results showed that prodigiosin inhibited the cells viability in time and concentration dependent characteristics at different concentrations. We found that anti-proliferative effect of prodigiosin was associated with apoptosis on HSC-2 cells by determinations of DNA fragmentation, Hoechst 33258 staining, caspases activity, and TNF-α was significantly changed when compare DMSO control group. In addition, activity of lactate dehydrogenase (LDH) release increased when the cells incubated with prodigiosin at various concentrations and times. These results suggested that prodigiosin treatment inhibited proliferation and induction of apoptosis in human oral squamous cell carcinoma HSC-2.