Activation of alternative complement pathway is presumed to be important pathogenically in IgA nephropathy since renal biopsies usually exhibit glomerular deposition of C3 and P (properdin). Surprisingly, little is known about plasma complement activation in this disease, and the plasma C3 and C4 concentrations are usually normal or increased. We quantitated C3 activation in 202 plasmas from 81 patients with IgA nephropathy using a sensitive new assay that detects a neoantigen (iC3b-C3d neoantigen) which appears when C3b is inactivated to iC3b, C3dg, or C3d. This assay accurately quantitates small amounts of in vivo C3 activation. The concentration of iC3b-C3d neoantigen in plasma was significantly increased, indicating C3 activation in 37% of the pediatric and 57% of the adult plasmas assayed. When data from serial determinations in the patients were analyzed, 75% of the adult and 57% of the pediatric patients had C3 activation on at least one occasion. Classical pathway activation, quantitated by C4 activation was found in 20% of the adult and 5% of the pediatric plasmas. No association was found between elevated iC3b-C3d neoantigen concentration and history of macroscopic hematuria, chronic renal insufficiency or degree of proteinuria. These studies show that complement activation can frequently be detected in the plasma of IgA nephropathy patients. However, the pathophysiologic significance of this complement activation remains to be determined.