Histopathologic criteria are usually sufficient for the accurate distinction of benign from malignant melanocytic lesions of the skin. A minority of cases, however, particularly Spitz nevi, continue to pose a vexing diagnostic challenge. Recent research, however, suggests that p27 (kip1), a cell cycle inhibitory protein, may prove helpful in predicting the biologic behavior of a diverse array of human neoplasms. We analyzed 63 melanocytic lesions of the skin (21 Spitz compound nevi, 21 compound nevi, 21 melanomas, and a variety of other benign and malignant cutaneous neoplasms as a control group) for expression of p27 (kip1). The distribution of immunoreactivity was analyzed by quantifying nuclear staining in each case without knowledge of the diagnosis or outcome. Clinical history and follow-up information were obtained by chart review. There was no difference in the expression of p27 between Spitz nevi (labeling index=38.4+/-4.0), compound nevi (labeling index=40.1+/-4.8), and melanoma (labeling index=42.3+/-5.1). Logistic regression failed to show any difference in p27 labeling index between the nevi and melanoma (p=0.736). These results indicate that antibodies to p27 are not useful in distinguishing between these melanocytic lesions.