C(6), a Borrelia burgdorferi-derived peptide, is used as the antigen in the C(6)-Lyme disease diagnostic test. We assessed retrospectively whether a fourfold decrease or a decrease to a negative value in anti-C(6) antibody titer is positively correlated with a positive response to treatment in a sample of culture-confirmed patients with either early localized (single erythema migrans [EM]; n=93) or early disseminated (multiple EM; n=27) disease. All of these patients had been treated with antibiotics and were free of disease within 6 to 12 months of follow-up. Results show that a serum specimen taken at this time was either C(6) negative or had a >or=4-fold decrease in C(6) antibody titer with respect to a specimen taken at baseline (or during the early convalescent period if the baseline specimen was C(6) negative) for all of the multiple-EM patients (P<0.0001) and in 89% of the single-EM patients (P<0.0001). These results indicate that a decline in anti-C(6) antibody titer coincides with effective antimicrobial therapy in patients with early localized or early disseminated Lyme borreliosis.