Recent refinements in molecular genetic typing have allowed the precise determination of the extensive polymorphism now recognized in class II major histocompatibility complex (MHC) genotypes. This could have important applications in Kawasaki syndrome (KS), where the relative contribution of genetic factors is now well known. Accordingly, 44 Caucasian, 13 Asian, and 5 American black patients, as well as 221 Caucasian controls were typed for HLA-DRB1, DRB3, DRB4, DQA1, DQB1, and DPB1 alleles by oligonucleotide probe hybridization of polymerase chain reaction amplified genomic DNA using probes and primers supplied by the 11th International Histocompatibility Testing Workshop. Among the 15 HLA-DRB1, 3 DRB3, 9 DQA1, 15 DQB1, and 19 DPB1 alleles examined, none were found to be significantly associated with KS, except for an increased frequency of HLA-DRB3*0301 in Houston Caucasian patients when compared to Houston Caucasian controls (38 vs 11%, pc = 0.012, RR = 5.0). Twelve patients developed coronary artery involvement of whom 7 had aneurysms and 5 had dilatation (8 Caucasians, 2 blacks, 2 Asians). No specific HLA class II allele was associated with this disease complication. Despite a regional association, our data fail to support a consistent role for MHC class II alleles in the pathogenesis of KS.