The objective of this study was to reassess the role of C4A null alleles in systemic lupus erythematosus (SLE) susceptibility after taking into account the association of DQA*0501 with this disease. The frequency of C4A null alleles in 82 SLE patients and 59 controls was determined using both immunofixation and a TaqI RFLP method. HLA-DQA and DQB alleles were identified by sequence-specific oligonucleotide typing. Empirical logistic analysis was used to assess the interactive effects of C4 and DQA alleles. It was found that the strongest association with SLE was for the combination of DQA*0501 and C4A*Q0 [odds ratio (OR) = 5.4, 95% confidence interval (CI) 2.5-11.7]. Both DQA*0501 (P = 0.02) and C4A*Q0 (P = 0.03) appeared to have significant individual effects on SLE susceptibility, with a significant statistical interaction between the two loci (P = 0.01). However, when anti-La antibody negative patients were examined only C4A*Q0 had a significant individual effect (P = 0.04). A significant statistical interaction between DQA*0501 and C4A*Q0 was again detected (P = 0.02). These results support the hypothesis that susceptibility to SLE is influenced by several genes with differing functions: HLA-DQA*0501 may predispose to autoantibody formation while C4A*Q0 impairs immune complex clearance.