Recently, health measurements have broadened to include the assessment of quality of life (QOL). This study was conducted to assess whether the short form of the World Health Organization (WHO) QOL questionnaire (WHOQOL-BREF) was an effective tool for measuring morbidity due to Schistosoma mansoni infection and whether it could detect an impact of treatment with praziquantel. A total of 724 adults 18–85 years of age were enrolled. At baseline, S. mansoni prevalence was 73.2% by stool examination and 75.4% by circulating cathodic antigen, and there was no association between infection status and WHOQOL-BREF scores. Six months after treatment, S. mansoni prevalence was lower and the proportion of persons with higher WHOQOL-BREF scores significantly increased among persons who were infected at baseline. However, a similar increase was observed in persons not infected at baseline. In areas of high prevalence, the WHOQOL-BREF may not be able to detect the benefits of schistosomiasis control programs.