To determine the efficacy of imiquimod cream, 5 , in the treatment of lentigo maligna (LM). Design: Open-label before-and-after interventional study. Setting: A multidisciplinary melanoma clinic at a major tertiary hospital. Patients: Forty-three patients with biopsy-proven LM of greater than 5 mm in diameter completed this study. Interventions: Imiquimod cream, 5 , was applied to the lesion 5 days a week for 12 weeks. The original lesion was excised with a 5-mm margin. Main Outcome Measures: The primary outcome was histopathologic evidence of LM in the excision specimen assessed independently by 2 of 3 dermatopathologists. Visible inflammation during treatment and macroscopic clearance were recorded. Results: When 5 of the 43 patients with discordant histopathologic assessment of the excision specimen were excluded, 20 of 38 patients (53 [95 confidence interval, 36 -69 ) demonstrated histopathologic clearance of LM after imiquimod treatment. Visible inflammation was significantly associated with histopathologic clearance (P=.04), but the positive predictive value was low (62 ). Macroscopic clearance showed some association with histopathologic clearance (P=.11). Dermatopathologist concordance for all 43 specimens was substantial ( =0.77; 95 confidence interval, 0.57-0.96). Conclusions: Imiquimod cream, 5 , has limited efficacy in the treatment ofLMwhendeterminedbyhistopathologic assessment of the entire treated area. The clinical signs of visible inflammation during treatment and apparent lesion clearance cannot be relied on to assess efficacy.