Background Because of its unique mechanism of action and safety profile, imiquimod, a topical immune response modifier, is used for many benign and malignant dermatologic conditions. Adverse effects are typically limited to treatment site erythema and erosion. Objective To describe a newly recognized adverse effect of imiquimod. Methods A 79-year-old woman being treated with imiquimod 5 days per week for a nodular basal cell developed a verrucous plaque over the treatment area after 7 weeks of therapy. Results Scouting biopsies demonstrated multiple comedones and ruptured epidermoid cysts. There was no evidence of residual basal cell carcinoma. Conclusions Imiquimod is a new and novel treatment option for cutaneous malignancies. We report its successful use in the treatment of a nodular basal cell carcinoma. The multiple comedones and ruptured epidermoid cysts are newly reported adverse effects of imiquimod therapy.