The safety and immunogenicity of a recombinant outer surface protein A (OspA) Lyme vaccine in patients previously diagnosed with Lyme disease was assessed in a dose-ranging, prospective study. Thirty healthy volunteers were consecutively assigned to receive three doses of 3, 10, or 30 µg of OspA vaccine at 0, 1, and 2 months. Subjects were seen 3 days after each vaccine dose and 1 month after completion of the three-dose schedule. Local side effects included soreness, induration, swelling, and redness. Transient systemic side effects occurred in 21 subjects, the majority of which (81%) were characterized as mild. Solicited symptoms included migratory mild arthralgias that lasted 24 h in 3 subjects. Side effects were not more evident after the second or third dose. Of the patients, 93% developed high-titer OspA antibodies. Thus, an OspA vaccine may be safe and immunogenic in patients with a history of Lyme disease.