Objective To investigate the effect of intralesional interferon on patients with severe Peyronie's disease. Patients and methods Thirteen patients with Peyronie's disease and associated penile deformity of greater than 12 months' duration were selected. Characteristics of the plaque and the degree of deformity were measured objectively. Ten patients received 1.5 MU of α2B-interferon intralesionally three times a week for 3 weeks. Three patients received similar volumes of intralesional saline. Results Six of the 10 patients who received interferon reported the complete disappearance of pain on erection and an improvement in the penile deformity. Although the objective improvement in deformity was relatively small, with a mean improvement of 20°, patients with a small plaque (<4 cm) had a better response. All those receiving inferferon had predictable but brief side-effects similar to the symptoms of influenza. Conclusion Intralesional interferon is safe and well tolerated and results in symptomatic and some objective improvement, especially in patients with smaller Peyronie's plaques.