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Abstract Studies have estimated the impact of the environment on malaria incidence although few have explored the differential impact due to malaria control interventions. Therefore, the objective of the study was to evaluate the effect of indoor residual spraying (IRS) on the relationship between malaria and environment (i.e. rainfall, temperatures, humidity, and vegetation) using data from a dynamic cohort of children from three sub-counties in Uganda. Environmental variables were extracted from remote sensing sources and averaged over different time periods. General linear mixed models were constructed for each sub-counties based on a log-binomial distribution. The influence of IRS was analysed by comparing marginal effects of environment in models adjusted and unadjusted for IRS. Great regional variability in the shape (linear and non-linear), direction, and magnitude of environmental associations with malaria risk were observed between sub-counties. IRS was significantly associated with malaria risk reduction (risk ratios vary from RR = 0.03, CI 95% [0.03–0.08] to RR = 0.35, CI95% [0.28–0.42]). Model adjustment for this intervention changed the magnitude and/or direction of environment-malaria associations, suggesting an interaction effect. This study evaluated the potential influence of IRS in the malaria-environment association and highlighted the necessity to control for interventions when they are performed to properly estimate the environmental influence on malaria. Local models are more informative to guide intervention program compared to national models.