Polymorphism of 3 complement genes (C4A, C4B, and BF) located within the major histocompatibility complex was studied in 48 biopsy-proven IgA nephropathy patients and 19 patients with Henoch-Schonlein purpura (HSP). Polymorphism was determined by immunoelectrophoretic techniques and functonal activity using an overlay of sheep cells in agarose and C4 deficient sera. The subjects were divided into 4 large groups according to the presence or absence of a C4 null allele (a gene producing no identifiable gene product): group 1 (no null variants), group 2 (one C4A null variant), group 3 (one C4B null variant), and group 4 (two null variants at either the C4A or C4B locus, that is, homozygous null). Patients had a significantly increased frequency of group 4 phenotypes (homozygous null); (12 of 67 patients, 17.8%) as compared to controls (4 of 102 patients, 3.9%, P = 0.0031). Both IgA (P = 0.045) and HSP patients (P = 0.003) had a greater frequency of a C4 homozygous null phenotype. The serum C4 concentration was higher in patients than in controls (740 mg/ml and 576 μg/ml, respectively, P = < 0.001) whether evaluated together or by C4 phenotypic group. The association between the presence of IgA nephropathy or HSP with a homozygous C4 null phenotype is of unknown significance but suggests a predisposition to development of HSP or IgA nephropathy for individuals with the C4 homozygous null phenotype.