Major histocompatibility complex (MHC) determinants are critical to the induction or suppression of immune response and have been shown to control the ability to produce antibodies in response to protein antigen. Hepatitis B vaccine commonly fails among patients with renal failure, but genetic factors that modulate response to this vaccination are not yet characterized. The availability of HLA Class II genotyping by hybridization with specific oligonucleotidic probes, following DNA amplification by the polymerase reaction (PCR), has made the analysis of HLA class II loci a reliable and practical approach. Antibody response to HBs and HLA class II oligotyping were assessed among 203 hemodialyzed patients having received a full course of vaccination. Twenty-two percent (N = 45) produced less than 10 IU (radioimmunoassay) of anti-HBs antibodies following the fourth injection. These nonresponder patients had a significantly decreased frequency of the DR2 haplotype compared to responder patients or to a group of 405 normal controls (8.9% vs. 21.5% and 26.2%, P < 0.01). The frequency of the DR3 haplotype was not increased among subjects with lower response. No significant difference appeared in the responder group. These results argue in favor of the presence of HLA-linked immune response gene(s) controlling humoral response to HBs antigen, rather than in favor of the presence of an immune suppressive gene.