Examination of the extracellular products of nephritis(+) and nephritis(-) group A streptococci revealed the presence of a 46-kD protein secreted by nephritogenic strains that binds to human plasmin. Immunological data revealed that this protein, called nephritis plasmin binding protein (NPBP), is not related to group A streptokinase nor to a recently described streptococcal dehydrogenase protein. The binding of human plasmin to this protein can be blocked by epsilon-amino caproic acid, indicating the importance of lysine groups in the binding process. Mutanolysin extracts of cell walls from these nephritogenic strains probed with anti-NPBP antibody were negative for cell wall-bound NPBP. Serological data with acute poststreptococcal glomerulonephritis (APSGN) and acute rheumatic fever sera indicated that the protein reacts preferentially with APSGN sera. Amino acid sequence analysis and immunological reactivity suggest NPBP is the streptococcal pyrogenic exotoxin B precursor, also previously described as zymogen (streptococcal proteinase precursor). The secretion of both group A streptokinase and a secreted plasmin binding protein in the same nephritogenic strain raises an intriguing hypothesis of the mechanisms of action of this protein in APSGN.