In the first field trial with synthetic malaria vaccine SPf66 in a large population naturally exposed to malaria, 9957 persons >1 year old and residing on the Colombian Pacific coast received three doses of the vaccine. To evaluate vaccine safety, clinical observations were made 30 min and 48 h after each immunization. There were no adverse reactions in 95.7% of cases. In the 4.3% of cases with adverse reactions, local induration and erythema were the most frequent. In a randomly selected group of vaccinees, anti-SPf66 antibody titers were measured after the third dose: 93% of the vaccinees raised antibodies to SPf66. Among these, 55% had titers >1:1600. These results demonstrate the safety and immunogenicity of the SPf66 vaccine in a large field trial.