Objective To investigate the natural progression of Borrelia burgdorferi infection among the human population in some natural foci in Xinjiang, China and the genotypes of B. burgdorferi. Methods In 2006, 119 human subjects, who were randomly selected from 1390 negative cases of 1406 individuals receiving a seroepidemiological survey of B. burgdorferi infection in the summer of 2002, as well as the 16 positive cases in the 2002 survey, were included in the study. Serum samples of each individual were collected in 2002 and 2006 and examined for the IgM and IgG to B. burgdorferi by Western blot, and a questionnaire survey was performed to investigate the frequency of manifestation of Lyme disease. In addition, urine samples were collected from the 135 subjects and examined by nest PCR to amplify 5S-23S rRNA intergenic spacer of B. burgdorferi;some of the PCR positive products were sequenced to determine the genotypes of B. burgdorferi. The PCR detection results were compared with the serological test results. Results Of the 1406 serum samples in 2002, 16 (1.14%) were positive for B. burgdorferi antibodies. In the 16 positive cases, 12 were positive for IgM, 2 were positive for IgG, and 2 were positive for both IgM and IgG. In 2006, 7 (43.75%) of the 16 positive cases in 2002 became seronegative, 4 IgM-positive cases became IgG-positive, and 5 cases remained IgM-positive. Of the 119 negative cases in 2002, 58 (48.74%) became seropositive, including 14 IgM-positive cases, 25 IgG-positive cases, and 19 IgM-and IgG-positive cases, and 2 cases had a confirmed diagnosis of Lyme disease. In 2006, 67 (49.63%) of the 135 subjects were positive for B. burgdorferi antibodies, including 58 newly found cases and 9 cases that remained positive since 2002. Asymptomatic IgG positive seroconversion rate was 34.07% (46/135) (in 2002, 4 IgM-positive cases became IgG-positive; in 2006, 25 negative cases became IgG-positive and 19 negative cases became IgM-and IgG-positive, and 2 cases had a confirmed diagnosis of Lyme disease). Only 3 (2.22%) of the 135 subjects developed Lyme disease. Of the 135 urine samples, 22 (16.30%) had positive results in PCR detection. The sequence analysis of 8 PCR positive products revealed that 7 of them were B. garinii and the other was B. afzelii. Conclusion Most cases of B. burgdorferi infection are asymptomatic among the human population in the natural foci of Xinjiang, and this infection rarely results in Lyme disease. The most and second most frequent genotypes of B. burgdorferi among Xinjiang population are B. garinii and B. afzelii.