OBJECTIVES: We investigated the long-term impact of early childhood malaria prophylaxis on cognitive and educational outcomes. DESIGN: This was a household-based cluster-controlled intervention trial. SETTING: The study was conducted in 15 villages situated between 32 km to the east and 22 km to the west of the town of Farafenni, the Gambia, on the north bank of the River Gambia. PARTICIPANTS: A total of 1,190 children aged 3-59 mo took part in the trial. We traced 579 trial participants (291 in the prophylaxis group and 288 in the placebo group) in 2001, when their median age was 17 y 1 mo (range 14 y 9 mo to 19 y 6 mo). INTERVENTIONS: Participants received malaria chemoprophylaxis (dapsone/pyrimethamine) or placebo for between one and three malaria transmission seasons from 1985 to 1987 during the controlled trial. At the end of the trial, prophylaxis was provided for all children under 5 y of age living in the study villages. OUTCOME MEASURES: The outcome measures were cognitive abilities, school enrolment, and educational attainment (highest grade reached at school). RESULTS: There was no significant overall intervention effect on cognitive abilities, but there was a significant interaction between intervention group and the duration of post-trial prophylaxis (p = 0.034), with cognitive ability somewhat higher in the intervention group among children who received no post-trial prophylaxis (treatment effect = 0.2 standard deviations [SD], 95% confidence interval [CI] -0.03 to 0.5) and among children who received less than 1 y of post-trial prophylaxis (treatment effect = 0.4 SD, 95% CI 0.1 to 0.8). The intervention group had higher educational attainment by 0.52 grades (95% CI = -0.041 to 1.089; p = 0.069). School enrolment was similar in the two groups. CONCLUSIONS: The results are suggestive of a long-term effect of malaria prophylaxis on cognitive function and educational attainment, but confirmatory studies are needed.