Two clinical lots of alum-adsorbed SPf66 vaccine produced in the United States were evaluated in separate, open-label, Phase I clinical trials involving 15 healthy, malaria-naive, 18–45-year old men and women. Subjects received 2 mg doses subcutaneously in alternate arms at 0, one, and six months. Safety was assessed by monitoring local and systemic reactions and laboratory parameters. The most common side effects were erythema and local tenderness at the site of injection, which increased in frequency with subsequent doses of vaccine. These local reactions were considered mild and resolved within 24–48 hr. Eleven of 14 volunteers who received all three doses of vaccine seroconverted by enzyme-linked immunosorbent assay. The distribution of high, medium, and low nonresponders was comparable with that seen in trials of Colombian-produced vaccine. One high responder developed antibodies reactive with asexual stage parasite antigens by immunofluorescence and immunoblot. The results indicated that at full adult doses, SPf66 of U.S. origin is mildly reactogenic and induces immune responses similar to those reported for SPf66 of Colombian origin.