To ensure the removal of all melanomas at an early phase, a number of benign lesions are currently excised for diagnostic evaluation. Nevertheless, little is known about the frequency of melanomas missed (neither recognized nor excised for diagnostic verification) by early detection practices. This study aimed to investigate the diagnostic performance of a specialized pigmented lesion clinic (PLC) through linkage with a local cancer registry. In 1997, 1741 individuals resident in the area of Florence and Prato, Italy, the catchment area of the Tuscany Cancer Registry (RTT), were consecutively examined at a specialized PLC that has been running since 1992 at the Department of Dermatology of Florence. The outcomes of dermatological consultations retrieved from PLC case notes were compared with all the diagnoses of both in situ and invasive melanoma recorded by the RTT until 31 December 1999. The performance of the PLC in detecting cutaneous melanoma was evaluated in terms of sensitivity, specificity and predictive values, with the RTT data as the gold standard. In the population examined at the PLC, 15 newly incident melanomas, all histologically demonstrated, were recorded by the RTT. In 13 of the 15 cases, excision of the lesion had been recommended by PLC staff, while two melanomas, one in situ and one level II 0.60 mm thick invasive, were missed and were subsequently excised 586 and 824 days, respectively, after the first PLC examination. The clinical and dermoscopic features of the invasive lesion were in agreement with a 'featureless' melanoma, and lacked the well-established parameters of malignancy. A total of 67 benign pigmented skin lesions were excised for diagnostic evaluation. Thus the PLC showed a sensitivity in detecting cutaneous melanoma of 86.7% (95% confidence interval [CI] 85.1-88.3%), a specificity of 95.4% (95% CI 94.3-96.3%), a positive predictive value of 13.7% (95% CI 12.1-15.3%) and a negative predictive value of 99.9% (95% CI 99.7-100.0%). The ratio of melanomas to benign skin lesions excised was 1:5.1. In conclusion, specialized examination of pigmented skin lesions at the PLC offered good level of diagnostic performance, with an acceptable cost in terms of benign lesions removed and overall a low risk of missing melanomas.