Background: This study aimed to clarify associations between pain, psychological adjustment, and family functioning with health-related quality of life (HRQOL) in a sample of adolescents with sickle cell disease (SCD) utilizing teen- and parent-report. Methods: Forty-two adolescents (between the ages of 12 and 18) with SCD and their primary caregivers completed paper-and-pencil measures of pain, teen's psychological adjustment, and HRQOL. In addition, primary caregivers completed a measure of disease-related parenting stress. Medical file review established disease severity. Results: Pearson correlations identified significant inverse associations of pain frequency with physical and psychosocial domains of HRQOL as rated by the teen and primary caregiver. Generally, internalizing symptoms (i.e. anxiety and depression) and disease-related parenting stress were also significantly correlated with lower HRQOL. Examination of possible mediator models via a series of regression analyses confirmed that disease-related parenting stress served as a mediator between pain frequency and physical and psychosocial HRQOL. Less consistent were findings for mediation models involving internalizing symptoms. For these, parent-rated teen depression and teen anxiety served as mediators of the association of pain frequency and HRQOL. Conclusion: Results are consistent with extant literature that suggests the association of pain and HRQOL and identify concomitant pain variables of internalizing symptoms and family variables as mediators. Efforts to improve HRQOL should aim to address internalizing symptoms associated with pain as well as parenting stress in the context of SCD management. © 2008 Barakat et al; licensee BioMed Central Ltd.