Cultured human pancreatic cancer cells produce a number of growth factors, including transforming growth factor-alpha (TGF-alpha). These cells also overexpress the epidermal growth factor (EGF) receptor and exhibit a parallel increase in EGF receptor mRNA levels. TGF-alpha, which binds to the EGF receptor, is more potent than EGF in enhancing the anchorage-independent growth of several pancreatic cancer cell lines, including T3M4 cells. In contrast, EGF is more efficient than TGF-alpha with respect to EGF receptor downregulation and tyrosine phosphorylation in T3M4 cells. Further, T3M4 cells recycle EGF, but markedly degrade TGF-alpha. It is suggested that the production of multiple growth factors, the overexpression of the EGF receptor, the recycling of EGF, and the attenuated ability of TGF-alpha to downregulate the EGF receptor combine to enhance the growth advantage of human pancreatic cancer cells.