A multicenter, double-blinded, placebo-controlled study was done comparing a 30-microgram dose of a single protein recombinant OspA vaccine preparation with a saline placebo for efficacy in prevention of Lyme disease in humans. The OspA vaccine (30-microgram dose) or saline placebo was given intramuscularly at day 0, 1 month later, and 12 months later. Cases of possible Lyme disease were evaluated clinically and using culture, polymerase chain reaction and immunoblot assays. Safety data are being analyzed separately. 1,634 adult volunteers were enrolled at a single center in New York State. Vaccine efficacy during the first year was 40% and during the second 37%. Compared with placebo, the OspA vaccine significantly reduced the frequency of Lyme disease during the 2-year study period (P < 0.04, one-tailed Fisher's exact test). Vaccine efficacy was restricted to volunteers under 60 years old (50% vs 9%, P < 0.03, two-tailed Fisher's exact test). A recombinant OspA vaccine preparation was found to have moderate activity in preventing Lyme disease in adults under 60 years old from New York State. Reasons for vaccine failure need to be addressed and a risk benefit ratio calculated.