BACKGROUND: We conducted a double-blind, placebo-controlled, randomized trial to evaluate the preliminary efficacy and safety of imiquimod 5% cream treatment for cutaneous squamous cell carcinoma (SCC) in situ. METHODS: In all, 31 patients with biopsy-proven cutaneous SCC in situ were randomly assigned to placebo (vehicle) (n = 16) or imiquimod 5% cream (n = 15) daily for 16 weeks. Patients were assessed at week 28 for the primary end point, resolution of cutaneous SCC in situ. RESULTS: Of the 31 patients enrolled, 3 dropped out. Intention-to-treat analysis revealed 11 of the 15 patients (73%) in the imiquimod group achieved resolution of cutaneous SCC in situ, with no relapse during the 9-month follow-up period; none in the placebo group achieved resolution (P < .001). Imiquimod 5% cream was generally well tolerated and there were no serious adverse events. LIMITATIONS: Topical imiquimod 5% cream has proven to be an effective treatment for cutaneous SCC in situ. However, studies to define the ideal dosing regimen and cost-effectiveness are required before it can be accepted as a recognized therapy. CONCLUSIONS: In this controlled trial, patients with cutaneous SCC in situ receiving topical imiquimod 5% cream as monotherapy experienced a high degree of clinical benefit compared with placebo.