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Background: While school-aged children in low- and middle-income countries remain highly exposed to acute infections, programs targeting this age group remain limited in scale and scope. In this paper, we evaluate the impact of a new and comprehensive primary school-based health intervention program on student-reported morbidity and anthropometric outcomes in Lusaka, Zambia. Methods: A prospective matched control study identified 12 classes in 7 schools for the intervention and 12 classes in 7 matched schools as controls. Teachers in intervention schools were trained to deliver health lessons and to refer sick students to care. In addition, vitamin A and deworming medication were biannually administered to intervention students. The primary study outcome was student-reported morbidity. Secondary outcomes were weight, height, health knowledge, and absenteeism. Multivariable linear and logistic regression models were used to estimate program impact. Results: 380 students ages 4–16 were enrolled in the study in 2015, and 97% were followed up at endline in 2016. The intervention decreased the adjusted odds of self-reported acute illnesses by 38% (95% CI: 0.48, 0.77) and the adjusted odds of stunting by 52% (95% CI: 0.26, 0.87). It also increased health knowledge by 0.53 standard deviations (95% CI: 0.24, 0.81). No impact was found on weight (adjusted mean difference β = 0.17, 95% CI: - 1.11, 1.44) and student absenteeism (adjusted odds ratio (aOR) = 0.89, 95% CI: 0.60, 1.33). Conclusion: The results presented in this paper suggest that comprehensive school-based health programs may offer a highly effective way to improve students’ health knowledge as well as their health status. Given their low cost, a more general adoption and implementation of such programs seems recommendable. Trial registration: ClinicalTrials.gov Identifier: . [ABSTRACT FROM AUTHOR]