Abstract: Objective To investigate the effect of sodium phenylbutyrate (SPB) in modulating docetaxel resistance in human prostate cancer cells in vitro. Methods A PC3/docetaxel-resistant human prostate cancer cell line PC3/DTX was induced and examined for proliferation, viability, and cell inhibition rate in the presence of SPB. The concentration of concentration of docetaxel required to kill 50% of PC3/DTX cells incubated with 0, 1, 2, and 4 mmol/L SPB was determined using MTT assay. Cell apoptosis rate was analyzed with flow cytometry and the cellular expressions of p21, cyclin D1 and survivin proteins were detected using Western blotting. Results Treatment of PC3/DTX cells with 0, 1, 2, and 4 mmol/L of SPB for 48 h resulted in cell viabilities of (99.85±2.69)%, (84.68±3.87)%, (68.65±4.54)% and (43.54±5.69)%, and cell inhibition rates of (10.69±3.65)%, (25.78± 4.58)%, (54.68±3.98)% and (69.84±6.54)%, respectively (P<0.05). The concentration of docetaxel required to kill 50% of PC3/DTX cells cultured in the presence of with 0, 1, 2, and 4 mmol/L SPB was 135.98±2.69, 109.65±3.87, 87.65±3.84 and 64.62±2.98 nmol/L, respectively (P<0.05), and the cell apoptosis rates were (7.2±0.8)%, (10.2±0.9)%, (19.8±2.1)% and (27.4±2.5)%, respectively. SPB treatment promoted the protein expression of p21 and suppressed the expressions of cyclin D1 and survivin in PC3/DTX cells. Conclusion SPB can affect the expressions of p21, cyclin D1, and survivin in PC3/DTX cells and increase the sensitivity to the drug-resistant cells to docetaxel.