Transforming growth factor-beta 2 (TGF-beta 2) is a potent regulatory of proliferation and differentiation of both normal and malignant cells. In addition, TGF-beta 2 can exert a variety of immunosuppressive effects, suggesting that the production of this molecule contributes to impaired immunological surveillance of tumor development. In vitro, TGF-beta 2 expression has been demonstrated in cell lines derived from metastatic malignant melanocytes. but not in those derived from normal melanocytes. We sought to evaluate a potential role of TGF-beta 2 in the initiation or progression of malignant melanoma in vivo. We examined by nucleic acid in situ hybridization the expression of TGF-beta 2 mRNA transcripts in 124 melanocytic lesions including metastatic and primary invasive melanomas, melanomas in situ, nevi with architectural disorder and cytologic atypia, ordinary benign melanocytic nevi, and Spitz nevi. All metastatic melanomas and a majority (94%) of primary melanomas invasive to Clark's level III, IV, or V expressed TGF-beta 2 mRNA. A minority (41%) of Clark's level II primary invasive melanomas expressed this factor. All definitive melanomas in situ and nevi were negative. The results suggest that TGF-beta 2 expression in malignant melanoma may be a critical event in the development of deep invasion and metastases in malignant melanoma.