School children are increasingly recognised as an important target for malaria control. However, limited evidence exists on the relative benefits of alternative school-based malaria control interventions or how impact may vary according to transmission intensity. Nested within the first evaluation of school-based intermittent screening and treatment (IST), in a region of low-to-moderate transmission, this thesis aimed to investigate the influence of heterogeneity in underlying transmission risk and variation in the fidelity of the intervention on the impact and possible operational applications of IST. The thesis utilized data from a cluster-randomised trial, over two years, evaluating the impact of school-based IST on health and education of children in 101 schools in south coast, Kenya. In the intervention children were screened for Plasmodium falciparum infection using rapid diagnostic tests (RDTs) once a term, with those found RDT-positive treated with artemether-lumefantrine. Cross-sectional analysis of baseline data, indicated marked heterogeneity in P. falciparum infection and anaemia at school-level. P. falciparum infection was strongly associated with anaemia, but health status was not associated with educational performance. Subsequent analysis of the impact of IST showed no benefit on the primary health or education outcomes even when stratified by baseline Plasmodium prevalence, or number of treatments received. Latent class analysis suggested reasonable diagnostic performance of RDTs, with seasonal variability observed. Bayesian geostatistical analysis of the spatial and temporal heterogeneity of school-level P. falciparum infection highlighted the relative stability in observed heterogeneity, despite periodic treatment of infection. Analysis at the individual-level suggested overdispersion of P. falciparum infection with prevalence-based models showing a greater proportion of individuals repeatedly infected than expected even after accounting for exposure. Collectively, these findings indicate that, in such a locally heterogeneous transmission setting, school-based IST provided no health or education benefits, with a number of factors identified for lack of impact. The persistence of high infection levels in certain schools despite periodic treatment highlights the importance of fine-scale targeting with a need for community-wide coverage in high-risk clusters. Moreover, the findings suggest a potential role for school-level screenings in both the identification of communities for targeted control, and periodic monitoring of impact.