OBJECTIVE To establish a safe and efficacious dosing regimen for the treatment of primary nodular basal cell carcinoma (BCC) using 5% imiquimod cream. DESIGN Two phase 2 studies were conducted: a 6-week, randomized, open-label, dose-response study evaluating 4 dosing regimens and a 12-week, randomized, vehicle-controlled, double-blind, dose-response study evaluating 4 dosing regimens. SETTING Twenty-four public and private dermatology clinics in Australia and New Zealand (6-week study) and the United States (12-week study) participated. PATIENTS The study populations comprised 99 patients enrolled in the 6-week study and 92 patients in the 12-week study. Patients were at least 18 years old and had a biopsy-confirmed diagnosis of nodular BCC. INTERVENTIONS In the 6-week study, imiquimod was applied once daily for 3 or 7 days per week or twice daily for 3 or 7 days per week. In the 12-week study, imiquimod or placebo cream (vehicle) was applied once daily for 3, 5, or 7 days per week, or twice daily for 7 days per week. The entire tumor area was excised 6 weeks after treatment and examined histologically for evidence of remaining BCC. MAIN OUTCOME MEASURE The proportion of patients having no histologic evidence of BCC in the posttreatment excision specimen. RESULTS Dosing once daily for 7 days per week resulted in the highest clearance rate, with 25 (71%) of 35 and 16 (76%) of 21 patients showing clearance of their tumor in the 6- and 12-week studies, respectively. CONCLUSIONS Topical 5% imiquimod cream is well tolerated and most effective in treating nodular BCC when applied once daily for 7 days per week for either 12 or 6 weeks.