In Brazil, schistosomiasis continues to be an important health issue. The aim of this study was to identify factors associated with Schistosoma mansoni infestation. A cross-sectional study was performed to assess factors associated with S. mansoni endemicity in a municipality in Northeast Brazil with a history of reporting schistosomiasis. Participants were divided into four groups: 1) new S. mansoni cases (n = 44), 2) past history of S. mansoni treatment (n = 78), 3) immediate neighbors (n = 158), and 4) nearby controls (n = 35). Multiple comparisons analysis was performed. Subjects had a mean of 6.6 ± 3.9 years of education, and no difference was observed regarding family income (one-way ANOVA, P = 0.215). A total of 95.9% of the individuals had rudimentary cesspit as sanitary wastewater. The mean body mass index was 28.3 ± 5.1, with 41.0% and 24.1% overweight and obesity, respectively. Of note, 28.9% of adults had hypertension. Hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin were higher in the recent S. mansoni treated group (Wilks’ lambda, P < 0.001). Male gender was more prevalent in new S. mansoni cases (likelihood ratio, P < 0.001), close proximity to water collections was a risk for S. mansoni infestation (likelihood ratio, P < 0.001), and a better hematological status was observed in individuals recently treated with praziquantel. This study indicates the need to maintain surveillance for S. mansoni in low-transmission areas and the need to establish community-based interventions to control transmission.