Objective To observe the early efficacy and toxicity of gemcitabine plus tegafur, gimeracil and oteracil potassium (S-1) regimen (GS regimen) in patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure. Methods From July 2013 to December 2015, sixteen mCRPC patients who failed in the treatment of docetaxel-based chemotherapy in West China Hospital of Sichuan University were collected. And the patients were treated with gemcitabine 1 000 mg/m2 intravenously on Day 1 and S-1 40–60 mg/m2 orally dividedly twice daily on Day 1–10, which repeated every two weeks. The main outcome measures were total prostate-specific antigen (T-PSA) decline rate and pain remission rate. Results Of the 13 evaluable patients, the T-PSA decline rate≥50% was observed in 4 patients (30.8%). Among the 11 patients with bone pain, remarkable pain relief was observed in 4 cases (36.4%). Myelosuppression, gastrointestinal reaction, rash and fatigue were the commonly observed adverse reactions and the toxicity of chemotherapy was tolerable. Conclusion The GS regimen is active and tolerable in patients with mCRPC after docetaxel failure.