Abstract Background In Africa, inadequate health services contribute to the lack of progress on malaria control. Evidence of the impact of interventions to improve health services on population-level malaria indicators is needed. We are conducting a cluster-randomised trial to assess whether a complex intervention delivered at public health centres in Uganda improves health outcomes of children and treatment of malaria, as compared to the current standard of care. Methods/Design Twenty public health centres (level II and III) in Tororo district will be included; 10 will be randomly assigned to the intervention and 10 to control. Clusters will include households located within 2 km of health centres. The trial statistician will generate the random allocation sequence and assign clusters. Health centres will be stratified by level, and restricted randomisation will be employed to ensure balance on cluster location and size. Allocation will not be blinded. The intervention includes training in health centre management, fever case management with use of rapid diagnostic tests (RDTs) for malaria, and patient-centered services, and provision of artemether-lumefantrine (AL) and RDTs when stocks run low. The impact of the intervention on population-level health indicators will be assessed through community surveys conducted at baseline in randomly selected children from each cluster, and repeated annually for two years. The impact on individuals over time will be assessed in a cohort study of children recruited from households randomly selected per cluster. The impact on health centres will be assessed using patient exit interviews, monthly surveillance, and assessment of health worker knowledge and skills. The primary outcome is the prevalence of anaemia (haemoglobin <11.0 g/dL) in individual children under five measured in the annual community surveys. The primary analysis will be based on the cluster-level results. Discussion The PRIME trial findings will be supplemented by the PROCESS study, an evaluation of the process, context, and wider impact of the PRIME intervention which will be conducted alongside the main trial, together providing evidence of the health impact of a public sector intervention in Uganda. Trial registration and funding This trial is registered at Clinicaltrials.gov (NCT01024426) and is supported by the ACT Consortium.