BACKGROUND: First and second-generation aromatase inhibitors have shown activity in patients with androgen-independent prostate carcinoma. These early-generation aromatase inhibitors are nonselective, however, and inhibition of other steroidogenic enzymes may contribute to their reported clinical activity. The authors conducted a Phase II clinical study of letrozole to determine the safety and efficacy of a potent and selective third-generation aromatase inhibitor in men with androgen-independent prostate carcinoma. METHODS: Forty-three men with androgen-independent prostate carcinoma were treated with oral letrozole (2.5 mg daily). Treatment was continued until progressive disease or Grade 3 toxicity developed. Response and progressive disease were defined according to recommendations of the Prostate Specific Antigen Working Group. RESULTS: In total, 380 weeks of treatment were administered to the 43 study patients. The median duration of treatment was 8 weeks. Forty men discontinued treatment due to progressive disease. Only one patient responded to treatment with a sustained decrease > 50% in serum prostate specific antigen (PSA) levels. Three other patients experienced transient minor decreases (< 50%) in serum PSA levels. There were no serious treatment-related adverse events. CONCLUSIONS: Selective aromatase inhibition with letrozole is not active in men with androgen-independent prostate carcinoma.