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Objective: To examine changes in quality of life (QoL) in adolescents receiving family problem-solving therapy (F-PST) following traumatic brain injury (TBI). Method: Adolescents hospitalized for moderate-to-severe TBI were randomized to 1 of 3 ten-session, 6-month long treatments: face-to-face F-PST (n = 34), therapist-guided online F-PST (n = 56), and self-guided online F-PST (n = 60). Participants included 96 boys and 54 girls, of whom 124 were White and 6 were Hispanic. Outcomes were assessed pretreatment and 6 and 9 months later. Adolescents and parents rated adolescent QoL and TBI-related symptoms on the PedsQL and Health and Behavior Inventory (HBI), respectively. We used mixed modeling to examine changes over time and moderators of treatment efficacy. Results: Therapist- and self-guided online groups demonstrated improvements in parent-proxy QoL from baseline to 9 months, Cohen's d = 0.75; p =.004 and Cohen's d = 1.30; p <.001, respectively. The face-to-face group had poorer parent-proxy QoL at 6 months (M = 62, SE = 3.4) than either the therapist- (M = 70.9, SE = 2.8) or self-guided online group (M = 71.1, SE = 2.6). There were no changes or group differences in self-reported QoL over time. Similar findings were observed on the HBI. Differential treatment effects on parent-proxy outcomes were found in boys versus girls and in those from single versus 2-parent households. Improvements in parent-proxy HBI ratings mediated QoL improvements. Conclusions: Both online treatments, but not face-to-face F-PST, were associated with clinical improvements, raising questions about our current delivery paradigm. Individual and family moderators of treatment efficacy underscore the potential of personalized treatment. This study suggests that both self- and therapist-guided online family problem-solving treatment are effective in improving quality of life in adolescents following moderate to severe TBI. Sex differences in treatment response, with boys benefiting more from therapist-guided family problem solving than girls, highlight the need to personalize treatment choices. Lack of improvement following face-to-face treatment suggest a need to reevaluate the current treatment paradigm and give greater consideration to telehealth approaches. [ABSTRACT FROM AUTHOR]