Large nested melanomas (LNM) are a rare subtype of nevoid melanoma consisting of large junctional melanocytic nests that are more common in older individuals and/or associated with sun damage. However, the presence of large melanocytic nests alone does not lead to a diagnosis of malignancy, as they can also be found in melanocytic nevi. LNM are challenging because they lack most classic histological features of malignancy and require thorough clinicopathological evaluation. This ambiguity calls for a critical reassessment of the current diagnostic criteria for the subclassification of benign or malignant within the spectrum of large nested melanocytic tumors (LNMT).18 LNMT and 6 special site control melanocytic nevi (SSMN), were studied using different approaches: clinical features, dermoscopy, histopathology, immunohistochemistry, array comparative genomic hybridization (aCGH) and mRNA sequencing analysis, with the aim of identifying novel and reproducible criteria for the recognition of LNM.Careful clinicopathological evaluation of the 18 LNMT led to the diagnosis of 7 LNM and 11 large nested melanocytic nevi (LNMN). Lentiginous spread and nest bridging were significantly associated with LNM after Holm-Bonferroni correction. Asymmetry, largest nest size, poor lateral demarcation, number of colors and dermoscopic structures, and PRAME immunostaining were more common in LNM, but did not reach statistical significance. 4/7 LNM and 9/11 LNMN lacked the BRAF V600E mutation. Regarding aCGH, no LNMN or SSMN cases had ≥ 3 CNVs, in contrast to 50% of LNM cases. Importantly, LNM and LNMN could be distinguished by differential mRNA expression of 9 genes.Our study demonstrates that there is a spectrum of large nested melanocytic tumors and that the clinicopathologic diagnosis of LNM, for which we support the term “late-onset nested nevoid melanomas”, can be significantly strengthened by the presence of lentiginous pattern, nest bridging, gene CNV and differential mRNA expression.