Pigmented labial macules (PLM) are clinical, dermoscopic and histopathological challenges.To describe and evaluate the utility of reflectance confocal microscopy (RCM) in PLM and to establish a correlation between dermoscopy, RCM, histopathology and immunohistochemistry.Prospective study of PLM from four tertiary referral centers of Dermatology. Fifty-one (biopsy proven) PLM were included in the study. Dermoscopic, RCM images and histopathological preparations were evaluated for malignant criteria. Diagnostic accuracy of RCM for melanoma diagnosis, RCM Lip Score previously reported and kappa values between techniques were calculated.Five melanomas and 46 benign PLM were included. Dermoscopically, melanomas exhibited more frequently 3 colors and 3 structures. With RCM, pagetoid spreading, epithelial disarray, continuous proliferation of atypical cells around papillae, non-homogeneously distributed papillae, marked cellular atypia and higher number of dendritic cells per papillae were more frequent in melanomas. The RCM Lip Score was significantly higher in malignant lesions. Good kappa values were observed in most of the evaluated features. A perfect sensitivity and specificity was obtained combining dermoscopy and RCM.A low number of melanomas were obtained.RCM improves lip melanoma diagnosis and the RCM Lip score represents a useful tool for the evaluation of a PLM.