M icrobial adhesion to the host tissue represents an early, critical step in the pathogenesis of most infectious diseases. Borrelia burgdorferi, the causative agent of Lyme disease (LD), expresses two surface-exposed decorin-binding adhesins, DbpA and DbpB. A decorin-deficient (Dcn^–/–) mouse was recently developed and found to have a relatively mild phenotype. We have now examined the process of experimental LD in Dcn^–/– mice using both needle inoculation and tick transmission of spirochetes. When exposed to low doses of the infective agent, Dcn^–/– mice had fewer Borrelia-positive cultures from most tissues analyzed than did Dcn^+/+ or Dcn^+/– mice. When the infection dose was increased, similar differences were not observed in most tissues but were seen in bacterial colonization of joints and the extent of Borrelia-induced arthritis. Quantitative PCR demonstrated that joints harvested from Dcn^–/– mice had diminished Borrelia numbers compared with issues harvested from Dcn^+/+ controls. Histological examination also revealed a low incidence and severity of arthritis in Dcn^–/– mice. Conversely, no differences in the numbers of Borrelia-positive skin cultures were observed among the different genotypes regardless of the infection dose. These differences, which were observed regardless of genetic background of the mice (BALB/c or C3H/HeN) or method of infection, demonstrate the importance of decorin in the pathogenesis of LD.