Erythrocyte CR1, a C3b/C4b-binding complement-regulatory protein, is sensitive to proteolysis in vitro. To test the hypothesis that in vivo erythrocyte CR1 reduction results from intravascular proteinase activities, we used enzyme-linked immunosorbent assays to measure gamma- crosslinked fibrin degradation products (D-dimers) as indicators of coagulation/fibrinolytic activity, and complexes of neutrophil elastase with alpha 1 proteinase inhibitor (E/A) as indicators of neutrophil enzyme release in malignant and inflammatory disorders. Erythrocyte CR1, measured by monoclonal anti-CR1 antibody binding, was inversely related to disease activity and blood proteinase markers. Levels of erythrocyte CR1 were significantly lower for patients with active versus remittent squamous and small cell lung cancers, Hodgkin's and diffuse large cell lymphomas, and acute myelogenous leukemias. In patients with active thoracic cancers, elevated D-dimer levels correlated with reduction of CR1. In patients with rheumatoid arthritis, CR1 reduction was correlated with elevated levels of elastase complexes. Our findings substantiate the relationship of acquired CR1 reduction to the activity of certain diseases and provide circumstantial support for the hypothesis that erythrocyte CR1 is lost to proteolysis in vivo. Although heritable differences in CR1 expression reduce the interpretability of single measurements of erythrocyte CR1 levels, disease-associated CR1 reduction may be a useful indicator of disorders with chronically increased blood proteinase activity.