BackgroundParasitic infections are still of considerable public health relevance, notably among children in low- and middle-income countries. Measures to assess the magnitude of ill-health in infected individuals, however, are debated and patient-based proxies through generic health-related quality of life (HrQoL) instruments are among the proposed strategies. Disability estimates based on HrQoL are still scarce and conflicting, and hence, there is a need to strengthen the current evidence-base.MethodologyBetween November 2011 and February 2012, a national school-based cross-sectional survey was conducted in Côte d'Ivoire. Children underwent parasitological and clinical examination to assess infection status with Plasmodium and helminth species and clinical parameters, and responded to a questionnaire interview incorporating sociodemographic characteristics, self-reported morbidity, and HrQoL. Validity analysis of the HrQoL instrument was performed, assessing floor and ceiling effects, internal consistency, and correlation with morbidity scores. Multivariate regression models were applied to identify significant associations between HrQoL and children's parasitic infection and clinical status.Principal FindingsParasitological examination of 4,848 children aged 5–16 years revealed Plasmodium spp., hookworm, Schistosoma haematobium, Schistosoma mansoni, Ascaris lumbricoides, and Trichuris trichiura prevalences of 75.0%, 17.2%, 5.7%, 3.7%, 1.8%, and 1.3%, respectively. Anemic children showed a significant 1-point reduction in self-rated HrQoL on a scale from 0 to 100, whereas no significant negative association between HrQoL and parasite infection was observed. The 12-item HrQoL questionnaire proofed useful, as floor and ceiling effects were negligible, internally consistent (Cronbach's alpha = 0.71), and valid, as revealed by significant negative correlations and associations with children's self-reported and clinically assessed morbidity.Conclusions/SignificanceOur results suggest that HrQoL tools are not sufficiently sensitive to assess subtle morbidities due to parasitic infection in Ivorian school-aged children. However, more advanced morbid sequelae (e.g., anemia), were measurable by the instrument's health construct. Further investigations on health impacts of parasitic infection among school-aged children and refinement of generic HrQoL questionnaires are warranted.