We studied the possible role of transforming growth factor-β 1 (TGF-β 1) in tumor invasiveness by analyzing the production and activation of TGF-β 1 in eight human oral squamous cell carcinoma cell lines.<BR>The rate of secretion of TGF-β 1 was measured with a [¹²⁵I]-TGF-β 1 radioreceptor assay. All human oral squamous cell carcinoma cells secreted TGF-β 1 into the culture media. Three cell lines secreted very high levels of activated TGF-19.1. When the invasion of a monolayer of lung endothelial cells was assayed in vitro, highly invasive cell lines were found to secrete activated TGF-β 1 at higher rates than weakly invasive cell lines. These findings suggested that the different invasiveness of these cell lines was associated with the rate of activated TGF-β 1 production. Highly invasive potential squamous cell carcinoma cells, such as SAS, Ca 9 -22, and OSC-20, were inhibited by treatment with neutralizing anti TGF-β 1-antibody. Furthermore, the invasiveness of weakly (T. T and HSC-2) and highly (SAS) invasive cells was enhanced by SAS culture media. Affinity labeling of [¹²⁵I]-TGFβ 1 to cell surface receptors revealed the two major affinity crosslinked bands (type I and II I). These experiments indicate that TGF-β may modulate the invasive potential of human oral squamous cell carcinoma cells by autocrine action.