Primary objective: To examine the predictive associations of family satisfaction, functional impairment, pain, and depression on health-related quality-of-life (HRQoL) among persons with traumatic brain injury (TBI) through structural equation modelling (SEM). Research design: Participants were part of a larger longitudinal study of adjustment following TBI. Direct and indirect effects of predictor variables on HRQoL were analyzed through SEM. Methods and procedures: The sample included 131 participants with TBI (89 men, 42 women) who had been discharged from an acute care hospital. The Sickness Impact Profile was administered to measure HRQoL at or beyond 24 months post-discharge. Predictor variable measures included the Functional Independence Measure, Family Satisfaction Scale and single items assessing the presence of pain and depression. Main outcomes and results: SEM revealed direct effects of functional impairment (p<0.001), family satisfaction (p<0.01), depression (p<0.05) and pain (p<0.01) on HRQoL. Indirect effects from functional impairment (p<0.05) and pain (p<0.05) to HRQoL through depression were also present. Conclusions: The presence of pain and depression, greater functional impairment and lower family satisfaction were predictively associated with lower HRQoL. Depression further mediated the effects of pain and functional impairment on HRQoL. The present study advances understanding of the ways in which pain, depression and functional impairment predict HRQoL. © 2013 Informa UK Ltd.