BACKGROUND: Schistosomiasis control relies on the continued effectiveness of praziquantel (PZQ), yet individual and spatial heterogeneity in PZQ efficacy in the context of repeated mass drug administration (MDA) remains poorly understood. This study aimed to identify individual and spatial determinants of PZQ efficacy against Schistosoma mansoni in rural Uganda. METHODS: We studied 3870 participants aged 5-90 years from 52 villages in Pakwach, Buliisa, and Mayuge districts in Uganda. Participants were recruited to the SchistoTrack cohort in January-February of 2022 and 2023. Participants received PZQ and were followed up four to five weeks later to assess cure using Kato-Katz (KK) microscopy and point-of-care circulating cathodic antigen (POC-CCA) tests. Logistic regression models were used to identify predictors of cure, defined as a 100% egg reduction rate (ERR). We explored a comprehensive set of 18 sociodemographic, biomedical, water, sanitation, and hygiene, and spatial factors. Subgroup analyses were conducted for adults (aged 18-90) versus children (aged 5-17). Spatial autocorrelation in the outcome and model residuals was assessed using join count statistics and Moran's I. RESULTS: Of 3870 clinical participants, 3704 (95.7%) received PZQ, and 3395 of these had complete clinical data. Among the 3395 treated participants, 1406 (41.4%) were infected with S. mansoni at baseline. The overall cure rate (ERR of 100%) was 76.3%, ranging from 68.9% to 85.4% across districts. Higher odds of cure were associated with older age (OR 1.34) and lower baseline infection intensity (moderate/heavy vs light OR 0.39-0.61). Greater height was associated with lower odds of cure (OR 0.99), which was driven by adults. Compared with Mayuge district, participants in Western districts had lower odds of cure (OR 0.48-0.53). In children, greater distance to water sites with snail presence was linked to higher odds of cure (OR 1.05 per 100m). Results were similar when using POC-CCA outcomes. Spatial clustering of treatment outcomes was observed by district, but no residual spatial autocorrelation remained after accounting for district effects. CONCLUSIONS: Incorporating spatial analyses, refining dose assessment, and strengthening post-MDA monitoring may help maintain PZQ effectiveness and support sustainable schistosomiasis control efforts.