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Objective To examine associations between disease-related, individual, and contextual risk factors and health-related quality of life (HRQoL) in a sample of youth with inflammatory bowel disease using a cumulative risk model framework. Methods Participants were 50 youth (58% male; M age = 15 years). Youth and parents completed measures of HRQoL, psychological functioning, and family functioning. Disease information was collected from medical record reviews. Medication adherence was electronically monitored via MEMS cap bottles. A cumulative risk index (CRI) was constructed based on disease activity, disease type, gender, anxiety/depression, medication adherence, general family functioning, disease-specific family functioning, and socioeconomic status. Results The CRI was associated with all youth- and mother-reported HRQoL domains. Furthermore, contextual domain factors were most consistently associated with youth and maternal reports of HRQoL. Conclusion These results show promise in supporting the value of the CRI in identifying potential risk factors for lower HRQoL in a cross-sectional sample.