Perkinsus marinus is responsible for disease and mortality of the American oyster, Crassostrea virginica. To investigate the interactions between P. marinus and oyster hemocytes, protease activity was measured in plasma of oysters collected 4 hr, 24 hr, 4 days, and 2 mo after experimental infection with P. marinus. A significant increase in protease activity was observed in oyster plasma 4 hr after injection with P. marinus, followed by a sharp decrease within 24 hr. Gelatin-impregnated gel electrophoresis showed the presence of 2 major bands (60 and 112 kDa) and 3 less prevalent bands (35, 92, and 200 kDa) with metalloproteinaselike activity in the plasma of noninfected oysters. Additional bands in the 40- to 60-kDa range, corresponding to P. marinus serine proteases, were observed in oyster plasma at early time points after infection. A transient, but significant, decrease in the activity of oyster metalloproteinases was observed at early time points after infection. Coincubation of oyster plasma with P. marinus extracellular products resulted in a decrease in oyster metalloproteinases and several P. marinus proteases. This study provides insights into the role of proteases in the pathogenesis of Dermo disease.