The frequency of the HLA-DR2 antigen in 33 patients with clinical symptoms and signs of Bannwarth's syndrome was 33%, which was not significantly different from the 29% occurrence in 505 control subjects. However, all 11 HLA-DR2-positive patients had elevated serum levels of IgG antibodies against Borrelia burgdorferi, and these were present in 45% of 22 HLA-DR2-negative patients (P = 0.004). In the 21 patients with anti-B. burgdorferi antibodies the frequency of HLA-DR2 was 52%, which is significantly higher than the frequency in the control group (P = 0.04). The diagnosis of Bannwarth's syndrome was serologically confirmed by a positive indirect immunofluorescence assay (IFA). A negative test result does not exclude the diagnosis, as has recently been demonstrated with more sensitive techniques. The association between HLA-DR2 and a positive IFA suggests that the IFA selects a subgroup of patients with Bannwarth's syndrome and a different immune response. We could not demonstrate differences in the clinical spectrum and outcome between the two groups.