PURPOSE: We investigate the prostate specific antigen (PSA) response rate with nilutamide as a second line hormonal agent in patients with advanced prostate cancer in whom androgen ablation failed. MATERIALS AND METHODS: From 1998 to 2001, 28 patients with hormone resistant prostate cancer were treated with nilutamide as second line hormonal therapy. Average patient age +/- SD was 72.9 +/- 9.1 years. Median time from diagnosis of cancer to hormone failure was 48 months (range 2 to 120). Median followup from initiation of nilutamide therapy was 26 months (range 15 to 44). All patients had previously received at least 1 antiandrogen (flutamide or bicalutamide) in addition to medical or surgical castration, which failed. RESULTS: Upon initiation of nilutamide therapy 18 of the 28 patients (64%) had an initial reduction in PSA and 8 (29%) sustained a PSA response (greater than 50% decrease) beyond 3 months (range 3 to 21). PSA response to nilutamide in patients with a previous antiandrogen withdrawal response versus nonresponse was 100% and 18%, respectively. In 10 of the 28 patients, (36%) PSA continued to increase. Interstitial pneumonitis developed, in 1 patient and 5 had nonspecific complaints (headaches, nausea, dizziness). During followup 6 of the 28 patients died 1 of whom was a nilutamide responder. No patient died while on nilutamide. CONCLUSIONS: Nilutamide can achieve a significant sustained PSA response with a favorable toxicity profile. Patients with a previous antiandrogen withdrawal response have a significantly greater chance of responding to nilutamide.