The purpose of this study was to determine whether set gene plays a role in the tumorigenesis of human colorectal adenocarcinoma and oral squamous cell carcinoma. We used the human colon carcinoma cell line Ls174 and oral squamous cell carcinoma cell line HSC3 to evaluate the effect of set suppression on cancer cell proliferation and apoptosis. Using real-time PCR, we examined set gene expression in human colorectal adenocarcinoma tissues and matched normal colorectal tissues. Thirty pairs of colorectal adenocarcinoma tissues and matched normal colorectal tissues were used for real-time PCR. We transfected human colon carcinoma cell line Ls174 and oral squamous cell carcinoma cell line HSC3 with siRNA against the set gene. The effect of set gene suppression on cancer cell proliferation and apoptosis were studied by MTT assay and flow cytometry. Real-time PCR indicated that set gene expression was up-regulated in 70% of tumor samples (21 out of 30 samples). siRNA2 sequences significantly decreased set mRNA levels in Ls174 and HSC3 cells. The inhibitory rate in the two cell lines was 55.91 and 71.57%, respectively. MTT assay revealed a 21.4% inhibition on cell proliferation in HS174 cells and a 20.2% inhibition in HSC3 cells. Flow cytometry data indicated that the cell apoptosis rate was 18.37% in Ls174 cells and 17.97% in HSC3 cells; these rates were significantly higher than those of the control groups. In conclusion, the set gene was found to play a role in the tumorigenesis of human colorectal adenocarcinoma. It may promote tumorigenesis by enhancing cancer cell proliferation and inhibiting cancer cell apoptosis.