Forty-one patients with 47 basal cell carcinomas (BCCs; 15 superficial, 26 nodular, and 6 sclerodermiform) were treated with 5% imiquimod cream once daily 5 times a week for 6 weeks in an open-label clinical trial. The overall response rate was 95.7%. Local side effects occurred in 68% of the patients as mild to moderate reactions with a clear association to the histological BCC subtype. Follow-up examinations for up to 17 months (median 10 months) showed scars in 14.9% of the patients and a recurrence rate of 6.6%. Overall, imiquimod represents a safe and effective treatment option for a selected cohort of BCC patients. Notably, by the second week of treatment 72.7% of BCC biopsies were histologically tumor-free, which correlated with a substantial decrease of the inflammatory infiltrate by up to 58% between weeks 3 to 6. This early imiquimod response might have important implications for the final definition of potentially shorter imiquimod treatment periods.