Objective To investigate the effects of p38 gene sliencing on the proliferation, invasion, cell cycle and sensitivity to sunitinib of human renal carcinoma cell line 786-O. Methods We designed two sequence-specific small interfering RNA(siRNA531 and siRNA659) targeting p38 gene and transfected them into renal carcinoma cell line 786-O. 786-O cells transfected with nonsense siRNA served as negative control and those cultured with transfection medium served as blank control. The change of p38 gene expression was observed by RT-PCR and the expression of p38 protein was detected by Western blotting analysis.The proliferation, sensitivities to sunitinib, invasion capabilities, and the cell cycle of 786-O cells were examined by CCK-8 assay, transwell chamber test and flow cytometry, respectively. Results RT-PCR and Western blotting analysis revealed that p38 expression in p38 siRNA group was significantly decreased compared with the controls. The cell proliferation rates were also significantly decreased 3-5 days after siRNA531 or siRNA659 transfection compared with the controls (P<0. 05, P<0. 01), and cells in the siRNA531 and siRNA659 groups become more sensitive to sunitinib compared with negative control group, with two IC₅₀ values being significantly lower than that of the negative control group ([3.2±0.3],[1.4±0.1] μmol/mL vs[5.4±0.2] μmol/mL; P<0.05). In addition, analysis of cell cycle demonstrated a marked G₀/G₁ arrest of the 786-O cells transfected with siRNA531 or siRNA659. We also noticed that 24 h after transfection, the cell invasion capabilities was significantly decreased in siRNA531 and siRNA659 compared with negative control (numbers of cells permeating septum:56.43±6.02, 34.00±8.12 vs 76.27±5.08; P<0. 01). Conclusion We have successfully suppressed p38 gene expression by specific siRNA, which can inhibit the proliferation and invasion of human renal carcinoma cell line 786-O and increase its sensitivity to sunitinib, paving a way for future treatment and targeted drug resistance of renal cell carcinoma.