Although the aetiology of chronic fatigue syndrome is controversial, evidence that infective agents including viruses may have a role in the development of the condition has led to studies seeking an association with the immunomodulatory HLA genes. In the present study, we sought to extend previous work using a well-characterized patient group and modern HLA genotyping techniques. Fifty-eight patients were phenotyped for HLA A and B by microcytotoxicity and genotyped for HLA DRB, DQB and DPB by PCR oligoprobing, and the frequencies of antigens so assigned were compared with those from a control group of 134. No significant differences in HLA frequencies were found between patient and control groups. Thus, this study does not confirm previous findings of an HLA association with chronic fatigue syndrome, suggesting that neither presentation of viral antigen by HLA class I nor antigen processing genes in the HLA region is a major contributory factor in the development of the disease.