Melanoma, the most fatal of all skin cancers, by unknown mechanisms overcomes the cytostatic effects of TGFβ, while maintaining the TGFβ signaling needed for its tumor promoting functions. Besides TGFβ, ectopic induction of the TGFβ family member Nodal has been reported in human melanoma to correlate with progression to metastatic growth. The same authors reported that a Smad2 morpholino antisense oligonucleotide delays Nodal-induced tumor growth of the aggressive melanoma cell line C8161 in xenograft assays. To investigate the underlying molecular mechanism, we compared C8161 melanoma cells with isogenic poorly metastatic C81-61 cells reportedly lacking Nodal expression. Unexpectedly, reverse transcription PCR, Western blot analysis using specific antibodies, and activity assays revealed that metastatic C8161 cells and many other human melanoma cell lines and tumors do not express Nodal, but frequently upregulate the related ligand Activin A. However, siRNA knockdown of Activin A did not reduce invasiveness of C8161 cells in matrigel, nor did the overexpression of Activin A in C81-61 cells increase it. The activity of Smad2,3 signaling was evaluated in the melanoma cell lines by a seriesWestern blot and reporter assays. The Smad signaling pathway was found to be attenuated in both C8161 and C81-61 cell lines, as only a small fraction of total Smad2,3 was detected in the nuclear fraction of the melanoma cells. In addition, little Smad3 signaling activity was observed by a Smad3-dependent luciferase reporter. To evaluate paracrine effects, human melanoma cells that do or do not express exogenous Activin A or Nodal were xenografted into nude mice. Neither Activin A nor Nodal enhanced metastatic growth in this assay. Inhibition of Activin A did also not alter metastasis formation. However, in the presence of the human fragment crytallisable region (Fc), Activin A seems to enhanced metastatic growth. Further studies are required to confirm these results, and to find the mechanism by which Activin A enhances metastatic potential.