Intradermal inoculation of the rabbit with Borrelia burgdorferi, sensu lato, results in the consistent development of erythema migrans (EM), dermal infection, and visceral dissemination of the spirochete. Within 5 mo, EM as well as dermal and visceral infection are cleared and the animals exhibit immunity to reinfection. This study compares infection-derived immunity with acquired resistance resulting from the administration of a lipidated recombinant outer surface protein A (OspA) vaccine presently undergoing human trial. 4 of 11 OspA vaccinated rabbits, challenged intradermally at each of 10 sites with 10(5) low passage B. burgdorferi, developed EM as well as dermal and disseminated infection. After identical challenge, 2 of the 11 infection-immune rabbits developed a dermal infection, but not EM or disseminated infection. Further, ELISA anti-OspA titers did not correlate with the status of immunity for either OspA vaccinated or infection-immune rabbits. Prechallenge ELISA anti-OspA titers were relatively low in the infection-immune group. This study demonstrates that a state of partial immunity to experimental Lyme disease may result that could potentially mask infection. Further, our data strongly suggest that immunogen(s) other than OspA is/are responsible for stimulating acquired resistance in the infection-immune rabbit.