BACKGROUND: Seasonal malaria chemoprevention is widely implemented in Sahel and sub-Sahel countries in Africa. Few studies have assessed the impact of the SMC on hospital admission and death when it is implemented in the health system. This retrospective study assessed the impact of seasonal malaria chemoprevention (SMC) on hospitalizations and deaths of children under 5 years of age during the second year of implementation of SMC in the health district of Ouelessebougou in Mali. METHODS: In February 2017, a survey was conducted to assess hospital admissions and deaths in children under 5 years of age in two health sub-districts where SMC was implemented in 2015 and two health sub-districts where SMC was not implemented. The survey reviewed deaths and hospitalizations of children under 5, in the four health sub-districts. The crude and specific incidence rates of hospitalizations and deaths were determined in both groups and expressed per 1000 children per year. A negative binomial regression model and a Cox model were used to estimate the relative risks of hospitalization and death after adjusting for confounders. The R software was used for data analysis. RESULTS: A total of 6638 children under 5 years of age were surveyed, 2759 children in the SMC intervention areas and 3879 children in the control areas. All causes mortality rate per 1000 person-years was 8.29 in the control areas compared to 3.63 in the intervention areas; age and gender adjusted mortality rate ratio 0.44 (95% CI 0.22-0.91), p = 0.027. The incidence rate of all causes hospital admissions was 19.60 per 1000 person-years in the intervention group compared to 33.45 per 1000 person-years in the control group, giving an incidence rate ratio (IRR) adjusted for age and gender of 0.61 (95% CI 0.44-0.84), p = 0.003. CONCLUSION: The implementation of SMC was associated with a substantial reduction in hospital admissions and all-cause mortality. Trial registration ClinicalTrials.gov NCT02646410.