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Melanoma incidence has been rising steadily for decades, whereas mortality rates have remained flat. This type of discordant pattern between incidence and mortality has been linked to diagnostic drift in cancers of the thyroid, breast, and prostate. Ancillary tests, such as fluorescent in situ hybridization (FISH), are now being used to help differentiate melanomas from melanocytic nevi. Multicolor FISH has been shown to distinguish between these 2 with 86.7% sensitivity and 95.4% specificity. To assess the ability of FISH to differentiate melanomas with metastatic or lethal potential from those with an indolent disease course, we performed FISH with probes targeting 6p25, centromere 6, 6q23, and 11q13 on 144 primary melanomas with a minimal tumor thickness of 2 mm and compared the development of metastatic disease and melanoma-specific mortality as well as relapse-free and disease-specific survival between FISH-positive and FISH-negative cases. Of the melanomas, 82% were positive by FISH according to previously defined criteria. The percentage was significantly higher (93%) in cases that developed systemic metastases (n=43) than in patients that did not (77%, n=101). FISH-positive primaries had a significantly increased risk of metastasis or melanoma-related death compared with FISH-negative cases odds ratio 4.11; confidence interval, 1.14-22.7 and odds ratio 7.0, confidence interval 1.03-300.4, respectively. FISH status remained an independent parameter when controlling for known prognostic factors. These data indicate that the group of melanomas diagnosed with routine histopathology that lack aberrations detected by FISH is enriched for melanomas with a more indolent disease course. This suggests that molecular techniques can assist in a more accurate identification of tumors with metastatic potential.