We tested the hypothesis that cross-reactivity between the outer surface protein A (OspA) of Borellia burgdorferi and human leukocyte function antigen (LFA) type 1 mediates chronic autoimmune sequelae of Lyme disease. T cell response was studied in subjects with Lyme disease presenting with erythema migrans alone (n=36), erythema migrans with neurological disease (n=12), and chronic Lyme disease syndrome (n=20), as well as healthy control subjects from Lyme-endemic (n=50) and -nonendemic (n=18) regions. Antigens included recombinant OspA and OspC (all strain B31) and human LFA-1 peptide (IYVIEGTSKQDLTSF). Proliferation to OspA was detected in 11 (28%) of 39 of subjects presenting with erythema migrans, which increased to 50% at 4 weeks of follow-up. Reactivity to OspA and LFA-1 was significantly correlated (P<.001) and was observed in 18 (78%) of 23 of OspA-responsive subjects. However, there was no correlation between T cell response to human LFA-1 peptide and clinical status.