Current hypotheses suggest that both the plasmin system and metalloproteinases are involved in tumor invasion of basement membrane. In this study, we demonstrate that plasmin can directly degrade native and denatured type IV collagen in solution as well as in tissue sections. Tumor cell lines secreted plasminogen activators into culture supernatants that activated exogenous plasminogen to degrade type IV collagen in zymograms and to remove collagen IV immunoreactivity from tissue sections. Inhibition of metalloproteinase activity in culture supernatants by EDTA did not interfere with plasminogen-mediated type IV collagen degradation. We propose that tumor cells possess a mechanism for the degradation We propose that tumor cells possess a mechanism for the degradation of basement membrane type IV collagen, independent of metalloproteinases but dependent on plasminogen conversion to plasmin.