Combined melanocytic nevi can contain a phenotypically distinct population of large atypical epithelioid cells in a background of smaller banal-appearing melanocytes. On the basis of the pattern of proliferation and degree of pigmentation, nevi with this pattern have been referred to as nevi with an atypical epithelioid cell component (N-AECC). When N-AECC display sheet-like or an expansile nodular growth pattern, notable cytologic atypia, and any level of mitotic activity, they can be difficult to distinguish from melanoma. The clinical history and appearance of these lesions may similarly raise concern for melanoma. In view of this diagnostic problem, we present 28 cases of N-AECC from our dermatopathology consultation and in-house practice. All 28 cases were found to be negative on the basis of fluorescence in situ hybridization (FISH) for imbalanced chromosomal aberrations commonly found in melanoma. The clinical outcomes showed a benign clinical course for all cases for which the outcome information was available. FISH analysis also revealed that, in 4 of 28 cases (14%), the AECC of the lesion demonstrated polyploidy localized to the large epithelioid cell component. This is likely more common among cases of N-AECC that have an atypical spitzoid epithelioid cell component, particularly those with obvious senescent nuclear changes. Care must be taken to avoid the pitfall of misinterpreting these FISH findings as changes consistent with melanoma. The use of ancillary testing methods including FISH may be beneficial in improving the diagnostic accuracy involved in making the distinction of N-AECC from melanoma. Further, we report a novel finding of polyploidy seen in certain cases of benign N-AECC.