We investigated the efficacy and safety of intralesional interferon α-2b for the treatment of Peyronie’s disease. A total of 117 consecutive patients with a mean age of 55.1 years who had Peyronie’s disease were enrolled in a single-blind, multicenter, placebo controlled, parallel study to determine the efficacy and safety of intralesional interferon α-2b therapy (Schering, Kenilworth, New Jersey), including 62 who received placebo and 55 who received interferon α-2b. Saline (10 ml) in controls and interferon α-2b (5 × 10 6 U) were administered biweekly for 12 weeks. Each patient was evaluated for penile curvature, plaque size and density, penile pain, erectile function and penile hemodynamics before and after study completion. Improvement in these parameters was statistically compared between the groups. A total of 53 patients in the control arm and 50 in the interferon α-2b arm completed the study. Improvement in penile curvature, plaque size and density, and pain resolution was significantly greater in patients treated with interferon α-2b vs placebo. The increase in mean International Index of Erectile Function scores was not significantly different between the groups. Penile blood flow improvement was observed in interferon α-2b treated patients but not in those who received placebo. The decrease in the number of penile vascular pathologies was significantly higher in interferon α-2b cases. Side effects, mostly flu-like symptoms, which were frequently noted in patients on interferon α-2b, were mild to moderate in degree and of short duration. This single-blind, multicenter, placebo controlled, parallel study demonstrates that intralesional interferon α-2b at a dose of 5 × 10 6 units biweekly for 12 weeks is effective and safe as minimally invasive therapy for Peyronie’s disease.