Based on evidence of an increased rate of respiratory infections in sudden infant death (SID) infants as well as the observation of familial occurrence, we analysed in a retrospective study class II and class III genes of the major histocompatibility complex in 40 cases of SID by Southern blot analysis of DNA obtained post mortem from tissue samples. In 24 cases, the parents were interviewed and confirmatory human lymphocyte antigen (HLA) and DNA typing was carried out. Using HLA-DRß and-DQß probes, no evidence of an abnormal HLA-DR frequency distribution in SID infants was detected (P=0.97). Using DNA probes for the tandemly arranged complement C4 and steroid 21-hydroxylase genes, an increased number of C4B gene deletions in SID cases was found. The increase in C4 gene deletions was significant (P=0.0125) in infants with recurrent infections. These data indicate a possible role of partial C4 deficiency as a genetically predisposing risk factor in SID.