Among Borrelia spirochetes carried by hard ticks belonging to the various Ixodes species, at least 10 species can be distinguished. Of these, Borrelia burgdorferi sensu stricto is involved in human Lyme borreliosis in North America and Europe, and Borrelia garinii and Borrelia afzelii in human disease in Europe and Asia. The pathogenetic significance of the other species is uncertain. Although some of the Borrelia species are restricted to certain tick species, Ixodes ricinus, the vector of Lyme borreliosis in Europe, can be infested by at least five different species, including all three pathogenic species. There is evidence that different Borrelia species are preferentially found in different hosts: In Europe, B. afzelii is frequently found in small mammals, whereas B. garinii and Borrelia valaisiana are often found in birds. This could very well be related to differential sensitivity of these species to complement-mediated bactericidal activity of different hosts. Borrelial complement regulator acquiring proteins, among them OspE or Erp proteins, bind to host factor H and related proteins, and this binding protects against activation of complement by the spirochetal surface. The binding is different for proteins originating from different species and is also depending on the host origin of factor H. In Europe, B. garinii is mainly found in neuroborreliosis, whereas in skin disease B. afzelii is more frequently found. The reason is unclear. The majority of human sera cross-react between proteins of different Borrelia species, but some sera react only with proteins from one of the species. This holds especially for reactivity with OspC. A vaccine against B. burgdorferi sensu stricto has been licensed, but was recently redrawn from the market because of commercial reasons. A vaccine protecting against all three pathogenic species is not yet available.