Borrelia burgdorferi sensu lato, the causative organism of Lyme borreliosis, is a heterogeneous group of spirochetes, consisting of at least three pathogenic species. To test the hypothesis that the genetic heterogeneity is the reason for the clinical differences, we investigated whether the experimental disease induced by European isolates is different from that induced by American isolates. Two American isolates of species B. burgdorferi sensu stricto were compared with three European isolates, two of species B. garinii, and one of species B. afzelii. The patterns of infection, immunity, and inflammation induced by the different species was distinctive. Inflammatory cells and levels of antibody in B. garinii- and B. afzelii-infected animals were lower than in B. burgdorferi s.s.-infected animals, whereas levels of spirochetal infection in the skin and nervous system were higher in the former group of animals. These data demonstrate that B. burgdorferi s.s. strains are more infective and inflammatory, whereas B. garinii and B. afzelii strains can survive the adaptive immune response to a greater degree and persist at greater numbers in the skin and nervous system. The results explain to a large extent the disparities between LNB in humans in the United States and Europe.