Objective  To investigate the effect of picropodophyllin(PPP) on proliferation and cell cycle of human colorectal cancer cell line HCT-15 and to clarify the related mechanism.   Methods  Different concentrations of PPP were used to treat HCT-15 cells, the proliferative activity of HCT-15 cells was detected by cell courting kit-8(CCK-8). Morphological changes of HCT-15 cells were observed under inverted microscope. Flow cytometry was used to detect the changes of HCT-15 cell cycle and Western blotting was used to detect the expression of proliferating cell nuclear antigen (PCNA) and cell cyclinD1.   Results  The result  of CCK-8 assay showed that PPP inhibited the proliferation of HCT-15 cells in a dose-time-dependent manner. Under the inverted microscope, it was found that the HCT-15 cells lost their original shape and became round, the refractive index decreased, and the number of living cells decreased significantly. Flow cytometry showed that the proportion of G₂/M cells increased significantly, and the proportion of G₀/G₁ phase and S phase cells decreased significantly. Western Blot result  showed that the expression of PCNA, cyclinD1 protein was significantly decreased.   Conclusion  PPP significantly inhibited the proliferation of human colorectal cancer HCT-15 cells, suggesting that the mechanism might be to block the cells in G₂/M phase by down-regulating the expression of PCNA, cyclinD1 protein.