Increased production of transforming growth factor β (TGF-β) coupled with resistance to the growth-inhibitory effects of TGF-β is characteristic of several types of neoplasia including human melanoma. In select epithelial malignancies, lack of TGF-β-induced growth inhibition is associated with disruptions of TGF-β-dependent SMAD signaling and transcription. In contrast, the results of the present study indicate intact SMAD-dependent transcription in human melanoma cells, regardless of their proliferative response to exogenous TGF-β. Furthermore, in some melanoma cell lines constitutive SMAD-dependent transcription was observed, which was due in part to endogenous TGF-β. These results establish that resistance of melanoma cells to TGF-β-induced growth inhibition occurs independently of intact TGF-β receptor/SMAD-mediated transcriptional regulation. They also suggest that melanoma-derived TGF-β may exert autocrine effects on SMAD-sensitive target genes.