Background: The accuracy of digital epiluminescence microscopy (D-ELM) as an adjunct to clinical examination for the diagnosis of pigmented skin lesions (PSLs) has seldom been evaluated. Objective: To compare the accuracy of the combined clinical/D-ELM (C/D-ELM) examination with that of the clinical examination alone. Methods: A total of 3,372 PSLs from 1,556 consecutive patients referred to a skin cancer clinic underwent clinical examination and a combined C/D-ELM examination. The reference diagnosis was established using the histology report of known surgical excisions plus a cancer-registry-based follow-up (duration 18 months) of benign C/D-ELM diagnoses. The two diagnostic approaches were compared for sensitivity, predictive value and false-positive rate. Results: The series included 55 melanomas and 43 basal cell carcinomas. About 50% of malignant misdiagnosed cases were identified solely through the cancer registry. The C/D-ELM diagnosis showed a greater sensitivity for melanoma <0.76 mm thick (83 vs. 46% for clinical examination alone; ratio, 1.82) and basal cell carcinoma (79 vs. 49%; ratio, 1.62), a greater predictive value for melanoma (81 vs. 53%; ratio, 1.53) and a reduced total false-positive rate (0.3 vs. 0.9%; ratio, 0.31). Conclusion: D-ELM showed a potential to improve the clinical diagnosis of PSL.