Histologic, molecular, and epidemiologic data suggest that cutaneous melanomas arise through diverse causal pathways, one of which appears mediated by chronic sunlight exposure, and another associated with a nevus-prone phenotype. To further explore etiologic heterogeneity, we compared expression of key melanoma-related proteins according to histologic characteristics of the tumors and epidemiologic risk factors among a sample of 129 patients newly diagnosed with melanoma. Tumor tissue was stained with antibodies to phospho-mitogen-activated protein kinase (P-MAPK), Brn-2, retinoblastoma protein (pRb), p53, and p16. Using logistic regression analysis, we estimated the odds ratio (OR) and 95% confidence interval (95% CI) of protein expression associated with factors of interest. Except for pRb, candidate protein expression was detected in fewer than half the melanomas examined (P-MAPK, 39%; Brn-2, 30%; p53, 24%; p16, 41%). Strong pRb expression was associated with the presence of >20 solar keratoses (OR 6.5, 95% CI: 1.7-25.1) and melanomas with marked to moderate solar elastosis. p53 expression was positively associated with skin that readily burned (OR 3.8, 95% CI: 0.8-19.0) and was inversely associated with >60 nevi (OR 0.3, 95% CI: 0.04-1.5). Melanomas expressing P-MAPK were more likely to have contiguous neval remnants (OR 2.7, 95% CI: 1.1-6.5). P-MAPK and Brn-2 immunopositive melanomas were >/=4-fold more likely to be of the superficial spreading subtype. Brn-2 and p16 immunopositive melanomas had a greater Breslow thickness than melanomas that did not express these proteins. Brn-2, pRb, and p16 proteins were consistently coexpressed. These findings support the hypothesis that molecular profiles of melanoma reflect their histologic and epidemiologic characteristics, offering further evidence of more than one melanoma causal pathway. Exactly how the expression of each protein relates to the causal pathways needs to be further explored.