Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP-3), also known as K homology domain-containing protein overexpressed in cancer (KOC) and L523S, is a member of the insulin-like growth factor-II mRNA-binding protein family and is expressed during embryogenesis and in some malignancies. IMP-3 expression in melanocytic neoplasms has not been investigated. Fifty-six melanocytic neoplasms from 48 subjects were immunohistochemically studied using a monoclonal antibody against L523S/IMP-3. IMP-3 expression in melanoma was significantly higher than in Spitz nevi (P<0.05), and the staining intensity in the Spitz nevi was weak. IMP-3 expression in metastatic melanoma was significantly higher than in primary cutaneous melanoma with a Breslow depth </=1 mm (P<0.01). None of the benign nevi and dysplastic nevi expressed IMP-3. Our study demonstrates that IMP-3 is expressed in malignant melanoma but not in benign nevi, even when dysplastic features are present; IMP-3 is expressed in a significantly higher proportion of melanomas than Spitz nevi; and IMP-3 is expressed in metastatic melanomas significantly more than in thin melanomas. In conclusion, IMP-3 appears to be involved in the progression of malignant melanoma and may play an important role in the regulation of the biologic behavior of this tumor. Additionally, IMP-3 may have diagnostic utility in distinguishing melanoma from benign nevic cells, dysplastic nevi, and Spitz nevi.