Background: Confocal microscopy is a second-level examination for dermoscopically equivocal melanocytic lesions. However, the number of false-negative cases on confocal microscopy and the scenarios in which confocal microscopy may fail have not been fully elucidated. Objective: To calculate the percentage of false-negative melanomas upon reflectance confocal microscopy examination in a large series of cases. Methods: A retrospective analysis on 201 melanomas, evaluated for dermoscopic/confocal criteria of melanoma, was carried out. Results: Twenty-three melanomas out of 201 cases (11.4%) revealed a low 7-point checklist score. On confocal examination, 22 out of 23 lesions have been diagnosed correctly as melanomas. Only 1 lesion did not display melanoma features, neither upon dermoscopy nor upon confocal microscopy examination. Seven lesions out of 201 cases (3.5%) were judged as negative on confocal examination, even if 6 of them were diagnosed as melanomas by clinical and/or dermoscopic evaluation. After histopathological revision, these cases were grouped into 5 categories: (1) amelanotic melanoma (n = 1), (2) hyperkeratotic melanomas (n = 2), (3) lentiginous melanomas (n = 2), (4) melanoma with small pagetoid cells (n = 1), (5) spitzoid melanoma (n = 1). Conclusion: Confocal and dermoscopic examination, along with patient-related information and clinical history, can lead to an optimal patient management.

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