The autoantibody nephritic factor (NeF) leads to complement consumption in vivo and is associated with type II mesangiocapillary glomerulonephritis (MCGN II) and partial lipodystrophy (PLD). The third component of complement (C3) exists in two common allotypic forms, C3S and C3F, distinguished at the protein level by electrophoresis. An increased frequency of the rarer C3F allele has been reported in several autoimmune conditions, including one small series of patients with NeF. However, patients with NeF have low levels of circulating C3 so that allotyping at the protein level is difficult. The molecular basis of the S/F polymorphism has recently been established: a single base change at the DNA level encodes a single amino acid substitution at the protein level. A second polymorphism, closely linked to the first, is defined by the MoAb HAV 4-1, and is also due to a single base change. These polymorphisms can therefore be analysed at the DNA level. We have used the amplification refractory mutation system (ARMS), a modification of the polymerase chain reaction (PCR), to analyse these two C3 polymorphisms at the DNA level in 26 patients with NeF. The allele frequencies of C3S and C3F were 0.673 and 0.327 (predicted values 0.79 and 0.2, chi 2 = 4.813, P < 0.05), giving a relative risk of 2.1 for the development of NeF conferred by the presence of a C3F allele. The HAV 4-1 allele frequencies were (-) 0.71 and (+) 0.29, i.e. not significantly different than predicted from the linked C3S/F allele frequencies. This is the largest series of patients with NeF yet published, and our data confirm an association between C3F and NeF. Possible mechanisms for for this link are discussed.