Objective: To evaluate the performance of dermoscopists in diagnosing small pigmented skin lesions (diameter ≤6 mm) compared with an automatic multispectral computer-vision system. Design: Blinded comparison study. Setting: Dermatologic hospital-based clinics and private practice offices. Patients: From a computerized skin imaging database of 990 small (≤6-mm) pigmented skin lesions, all 49 melanomas from 49 patients were included in this study. Fifty randomly selected nonmelanomas from 46 patients served as a control. Main Outcome Measures: Ten dermoscopists independently examined dermoscopic images of 99 pigmented skin lesions and decided whether they identified the lesions as melanoma and whether they would recommend biopsy to rule out melanoma. Diagnostic and biopsy sensitivity and specificity were computed and then compared with the results of the computer-vision system. Results: Dermoscopists were able to correctly identify small melanomas with an average diagnostic sensitivity of 39% and a specificity of 82% and recommended small melanomas for biopsy with a sensitivity of 71% and specificity of 49%, with only fair interobserver agreement (κ=0.31 for diagnosis and 0.34 for biopsy). In comparison, in recommending biopsy to rule out melanoma, the computer-vision system achieved 98% sensitivity and 44% specificity. Conclusions: Differentiation of small melanomas from small benign pigmented lesions challenges even expert physicians. Computer-vision systems can facilitate early detection of small melanomas and may limit the number of biopsies to rule out melanoma performed on benign lesions.