Vaccination with recombinant outer-surface protein A (OspA) preparations has been highly successful in protecting laboratory animals against challenge by strains of Borrelia burgdorferi closely related to the one from which the OspA was derived. Humoral immunity is sufficient for protection. Against natural infection introduced by ticks, the vaccine-induced immune response may begin to take effect in the tick itself--i.e., before the spirochete enters the host--and may extend to a broader spectrum of strains of B. burgdorferi than are represented in the vaccine. Single recombinant OspA vaccine preparations are currently being evaluated in two large-scale efficacy trials in adults in the United States. Greater heterogeneity among B. burgdorferi strains in Europe than among those in the United States will likely necessitate the development of a vaccine containing antigens from multiple strains; a multivalent vaccine may or may not be needed in the United States.