The occasional familial occurrence of idiopathic nephrotic syndrome (NS) points to a genetic predisposition. Reports on associations with certain HLA class II antigens support this hypothesis. In order to define the immunogenetic background of NS more precisely, HLA class II allele frequencies in 161 children with NS were studied by restriction fragment length polymorphism (RFLP) typing. The patient cohorts consisted of 87 children from Southwest-France and 74 from Southwest-Germany. The control group consisted of 118 French and 101 German unrelated individuals from the same geographical areas. HLA alleles were defined in patients with steroid-sensitive (SS) and steroid-resistant (SR) NS and in controls. RFLP typing revealed that the previously reported association between SSNS and HLA-DR7 is confined to the RFLP split 7.1 (DRB1*07) with a combined relative risk (RRcomb) of 6.2. HLA-DQB typing showed an increased frequency of the allele DQB2b (DQB1*0201) (RRcomb = 7.8). HLA-DQA typing showed an association of SSNS with DQA3 (DQA1*0201,0301,0302) (RRcomb = 4.1). The highest RR (16.5) for SSNS was found in German patients who carried the two DRB1 specificities 17.1 (DRB1*0301) and 7.1 (DRB1*07). All associations were stronger in SS patients with frequent relapses or steroid dependency than in non- or infrequent relapsers. SR patients exhibited no significant associations with HLA class II alleles.