Genetic susceptibility to systemic lupus erythematosus (SLE) may vary amongst different populations. In UK patients, genes encoded in the HLA class II (DQA*0501/DRB1*0301) and class III [C4A*Q0 and tumour necrosis factor (TNF) polymorphisms] subregions appear to contribute to disease susceptibility. We have examined HLA-DRB1, C4 and TNF microsatellites in 50 Spanish SLE patients and 48 matched controls. HLA-DRB1*0301 was increased in patients but did not achieve statistical significance (41% vs. 25.5%). C4A*Q0 was not increased in patients, but C4B*Q0 allele frequency was significantly increased compared with the controls (29% vs. 6%; OR: 6.0). TNF c2 microsatellite allele frequency was also increased in SLE patients. The C4B null allele (C4B*Q0) appears to play an important role in SLE susceptibility in the Spanish population.