IgA nephropathy, the most commonly occurring type of chronic glomerulonephritis in individuals of European and Asian descent, exhibits marked heterogeneity of clinical signs and ultimate prognosis. Based upon their studies of regional clustering of the ancestors of related patients in eastern Kentucky, the authors have postulated the existence of an inherited disease susceptibility for IgA nephropathy. They examined serum concentrations of individual complement proteins and phenotypes for C3, C4A, C4B, and factor B (Bf) for related and unrelated patients with IgA nephropathy from Kentucky and for patients from the Mid-South region of Tennessee, Mississippi, and Alabama. In these populations, they have described partial complement deficiencies or specific phenotypes which may be associated with the disease. Their findings include the following: (1) partial deficiencies for C2, β1H (H), properdin (P), or C4 binding protein (C4BP) in four patients with end-stage renal disease, (2) an association between theC3*Fallele with IgA nephropathy in the combined group of unrelated patients from Kentucky and the Mid-South, (3) the occurrence of C4B deficiency in two siblings with IgA nephropathy, and (4) an association between C4A deficiency and poor outcome in patients with IgA nephropathy diagnosed as adults. In addition, the related patients differ from the unrelated patients from Kentucky with respect to frequencies ofBf*Fand the BfF (FF + FS + F1F + F1S) phenotype, suggestive of immunogenetic difference between these groups. Important functional differences exist between C4A and C4B isotypes and functional differences are also possible based upon C3 or Bf phenotype. The authors speculate that alterations in the function of the complement system may be important for the clinical expression of IgA nephropathy in an individual with inherited susceptibility for this disease.