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.