Background: Multiple treatments for squamous cell carcinoma in situ (SCCIS) of the penis have been used with variable success and morbidity. Surgery and destructive treatment modalities have significant risk of scarring, deformity, and impaired function. Objective: The purpose of this study was to determine whether topical imiquimod 5% cream is a potentially effective treatment for SCCIS of the penis and to qualify treatment associated morbidity. Methods: The case of a patient with extensive penile SCCIS is reported. The patient was treated with topical imiquimod 5%, administered daily until blistering occurred (2 cycles). Biopsy specimens were obtained to confirm tumor clearance. Results: One month after therapy was completed, no clinical or histologic evidence of residual tumor was found. Adverse effects of imiquimod included localized tenderness and erythema. No evidence of scarring, deformity, loss of function, or tumor recurrence was noted 18 months after treatment. Conclusion: Imiquimod 5% cream may represent an alternative treatment option for SCCIS of the penis. (J Am Acad Dermatol 2002;46:545-8.)