We evaluated the efficacy of intralesional interferon-α2b for Peyronie disease, reviewed the impact of the timing of therapy from disease onset and identified variables predictive of a response. We retrospectively reviewed the charts of patients treated with intralesional interferon-α2b from 2001 to 2012. Demographic information, disease characteristics, pretreatment and posttreatment penile duplex ultrasound findings, and objective measures were analyzed. Response was defined as a 20% or greater improvement in curvature. Statistical analysis was done to identify significant changes in variables and identify predictive factors. A total of 127 patients with a mean age of 55 years (range 25 to 76) and a mean±SD pretreatment curvature of 42.4±18.6 degrees underwent a median of 12 biweekly interferon-α2b injections (range 6 to 24). The median history of Peyronie disease was 2.0 years (range 0.5 to 23). Of the patients 54% responded to therapy with an overall mean improvement of 9.0 degrees (p<0.001). Patients with less than 30-degree curvature were most likely to experience a 20% or greater improvement with interferon-α2b (86% response, p<0.001). However, similar overall improvement in pretreatment curvature was noted in all cases. No statistically significant improvement was observed in penile vascular status or ultrasound parameters. The duration of Peyronie disease did not impact the change in curvature. Age, pretreatment curvature, vascular status, penile ultrasound findings, curvature site and International Index of Erectile Function (IIEF) score did not predict the response to therapy. Intralesional therapy with interferon-α2b resulted in significantly improved curvature without impacting penile vascular parameters. The absolute improvement in curvature was independent of pretreatment curvature or Peyronie disease duration.