We investigated anti–B burgdorferi antibody development for at least 1 year after antibiotic drug therapy in consecutive serum samples from a large series of patients with EM and correlated serologic results statistically with clinical data, including therapy-related variables. Our results are valid for European and American patients because the ELISA used is based on the flagellum antigen that is phenotypically stable between B burgdorferi strains of different geographic origin.23,24 We found that IgG and IgM antibody responses develop in 3 different profiles. The most common profile was PN. It was found in approximately half of the patients for the IgG and IgM antibody class. Because of the absence of a specific immune response it could be questioned whether the diagnosis of EM was correct in these patients. However, it is generally agreed that the clinical diagnosis of EM is reliable, and international guidelines do not require laboratory confirmation.4,37 In the present study, the clinical diagnosis was made in accordance with defined criteria3,4,38 by dermatologists with recognition rates of EM greater than 90%.39 Furthermore, the clinical diagnosis was substantiated by a typical histopathologic picture, and a positive polymerase chain reaction for B burgdorferi–specific DNA, or cultivation of B burgdorferi in 48% and 57% of these patients for IgG and IgM, respectively. Before therapy, IgG or IgM antibodies to B burgdorferi are lacking in approximately 50% of all patients with EM, particularly in those with shorter disease duration6,10,32,40 because seroconversion does not occur before 2 to 4 weeks of infection. In European patients with EM, infection with B burgdorferi is often limited to the skin,41 which could be another explanation for the absence of a systemic antibody response. After therapy, the lack of antibody development may be due to abrogation of the infection by adequate antimicrobial treatment.35,36 A number of treated, initially nonreactive patients may, therefore, remain seronegative. In uncontrolled earlier studies of a total of only 50 patients,14,29,34 40% to 100% of EM cases were found to remain seronegative during follow-up. The second profile, PP, was found in 11% of patients for the IgG class. In previous German studies,27,28 only 3% of patients remained seropositive on follow-up examinations, whereas others26,29,30,33,35 reported this phenomenon in 21% to 60% of their patients. The latter studies may have been skewed, however, by the inclusion of only seropositive patients30 or patients with extracutaneous symptoms.26 Persistence of IgM antibodies was detected in 12% of our patients, which compares well with an IgM persistence rate of 6% for more than 12 months in a pooled collective of 151 patients in 2 German therapy studies27,28 and with a rate of 10% for up to 20 years in 40 US patients with early (disseminated) Lyme disease.35 It could be speculated that persistent seropositivity indicates a continuing specific immune stimulation by noneradicated spirochetes with the potential consequence of ongoing symptoms or sequelae of Lyme disease. However, molecular and cultural proof of B burgdorferi elimination from the skin after antibiotic therapy19,42 make survival of B burgdorferi in antibiotically treated patients with EM unlikely. In the present study, PP was not correlated with a worse disease outcome, which contradicts such earlier theories.27,28 It may instead be assumed that sustained positive titers indicate a long-term serologic memory that results from an antigen-independent polyclonal activation and differentiation of memory B cells.35,43 The third profile was P-N an average of 5 months after treatment in approximately one third of the patients (30%) for IgG titers and less than half (43%) for IgM titers. Earlier studies found a decline in IgG antibodies in 10% to 43% and in IgM antibodies in 24% to 100% of investigated patients.26,29,30,34,35 However, direct comparison with our study is difficult owing to examination of only a few (partly) preselected patients across variable follow-up periods of 5 months to 10 years.