BACKGROUND: The role of gut inflammation for intestinal schistosomiasis remains poorly understood in chronically infected and repeatedly treated populations. METHODS: We conducted a cross-sectional study nested in the SchistoTrack cohort within Pakwach district, Uganda. In 2024, 640 participants aged 6-85 years were examined for Schistosoma mansoni by Kato-Katz. Fecal calprotectin (fCal) concentration was measured by enzyme-linked immunosorbent assays. Fecal calprotectin was analyzed as binary outcomes (detectable, ≥100 µg/g, >250 µg/g) and natural log-transformed continuous values. Co-endemic infections (malaria, HIV, hepatitis B [HBV]) and sociodemographic covariates were investigated in logistic regressions with covariate selection. RESULTS: 74.4% of participants had detectable fCal, 22.3% had fCal ≥100 µg/g, and 7% had fCal >250 µg/g. Schistosoma mansoni prevalence was 49.1%. Infection intensity was positively associated with all fCal outcomes (detectable: OR 1.20, ≥100 µg/g: OR 1.11, >250 µg/g: OR 1.26; continuous: β .06) while infection status was positively related to all but the continuous fCal outcome. HIV was associated with fCal ≥100 µg/g (OR 2.52), while malaria and HBV were uninformative. CONCLUSIONS: Schistosoma mansoni infections are characterized by persistent, clinically concerning levels of gut inflammation in chronically infected populations with repeated praziquantel treatment. Integration of fCal thresholds into clinical guidelines may improve management of schistosomiasis-related morbidity.