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Imiquimod has been used for treating lentigo maligna (LM) in selected cases when surgery is not an appropriate option because of functional or aesthetic impairment. Reflectance confocal microscopy (RCM) is a noninvasive method that has not been validated for monitoring the treatment of LM with imiquimod.We sought to evaluate the use of in vivo RCM to accurately monitor the response of LM to nonsurgical treatment with topical imiquimod.Twenty patients with confirmed facial LM, not amenable to surgical treatment or radiation therapy, were included prospectively. Clinical evaluation was performed by dermoscopy, RCM, and histopathology. Patients applied imiquimod 5% for 8 weeks. The affected area was assessed using the previously described LM score on RCM, and target sample biopsies were performed to confirm or discard RCM findings.Fifteen of the 20 patients (75%) presented histologic tumor clearance. Confocal microscopy identified 70% of these responders with no false-negative results, and when compared with histopathology, there was no significant difference in evaluating the response to imiquimod.The impossibility of examining the entire lesion by means of histopathology is a limitation.In vivo RCM evaluation was useful in accurately monitoring the response of LM to nonsurgical treatment with topical imiquimod in patients when surgery is contraindicated.