Ets-1 oncoprotein is a transcription factor known to regulate the expression of numerous genes important in extracellular matrix remodeling and angiogenesis. Up-regulation of Ets-1 has been shown to be important in a variety of human malignancies and to correlate with prognosis. To our knowledge, this oncoprotein has not been examined in melanocytic lesions. A series of 10 cutaneous melanomas and 24 benign melanocytic lesions with patient records were independently examined for diagnosis confirmation and immunohistochemical expression by two dermatopathologists. The immunohistochemical expression for Ets-1 (Novocastra, Newcastle upon Tyne, UK) was scored by an average of the mean labeling intensity; no nuclear staining = 0, weak nuclear staining = 1, moderate = 2, and intense = 3. Ets-1 expression was statistically assessed by the one-way analysis of variance (ANOVA) comparing the mean labeling intensity of melanoma to benign melanocytic nevi. All of the benign melanocytic lesions exhibited negative to weak nuclear staining, with an average mean labeling intensity of 0.4. Melanoma in situ exhibited moderate nuclear staining, for a mean labeling intensity of 2.0, whereas all conventional invasive melanomas exhibited moderate to strong nuclear staining, with a mean labeling intensity of 2.7. Metastatic melanoma exhibited very strong nuclear staining, with a mean labeling intensity of 3.0. Invasive desmoplastic melanoma, like melanoma in situ, showed moderate nuclear staining with a mean labeling intensity of 2.1. There was a trend toward more intense staining with melanoma progression. A statistically significant difference in the mean labeling intensity of Ets-1 was seen between invasive melanoma and benign melanocytic nevi (P <.0001). Ets-1 oncoprotein expression, however, does not distinguish among benign melanocytic lesions. Staining intensity and pattern might be a useful adjunct with histomorphology in distinguishing invasive melanoma from benign melanocytic nevi. Furthermore, Ets-1 expression may be an important pathogenic mechanism and predictor of aggressive biologic behavior of cutaneous melanoma, with a trend toward staining intensity increasing as Clark stage increases.