Topical imiquimod cream is increasingly applied in the treatment of lentigo maligna (LM), in particular for large lesions where surgery may lead to disfiguring scars. Published studies suggest that more frequent and prolonged treatment with topical imiquimod is associated with higher efficacy. In this study we prospectively treated 27 patients suffering from LM of the face with imiquimod 5% cream using an intensive treatment regimen consisting of daily applications for 12 weeks inducing at least 10 weeks skin inflammation. Twenty-four patients completed the treatment as recommended, 23 were available for follow-up (mean 39 months). Clinical and histopathological clearance was observed in 20 patients after on average 14 weeks of treatment. Notably, histopathological examination of a skin biopsy showed clearance of the LM in all 24 patients, including those who still showed some hyperpigmentation at 4 weeks off treatment. A clinical recurrence occurred in only 1 of the 24 treated patients. These findings suggest that the efficacy of imiquimod can be improved by implementing a more intensive treatment regimen. Randomized controlled trials are needed to confirm our results and establish the role of topical imiquimod in the treatment of LM.