Objective: To investigate the relation between posttraumatic stress (PTS) symptom severity and health-related quality of life (HRQoL) after severe traumatic brain injury (TBI). Design: Longitudinal prospective multicenter, cohort study on severe TBI in Switzerland (2007–2011). Setting: Hospital, rehabilitation unit, and/or patient’s living facility. Participants: Patients with severe TBI (N=109) were included in the analyses. Injury severity was determined using the Abbreviated Injury Score of the head region after clinical assessment and initial computed tomography scan. Interventions: Not applicable. Main Outcome Measures: HRQoL (Medical Outcomes Study 12-Item Short-Form Health Survey Physical and Mental Component Summaries) and self-reported emotional, cognitive, and interpersonal functioning (Patient Competency Rating Scale for Neurorehabilitation). Results: Multilevel models for patients >50 and ≤50 years of age revealed significant negative associations between PTS symptom severity and interpersonal functioning (P<.001 and P=.002), respectively. Among patients ≤50 years of age, PTS symptom severity was significantly associated with total functioning (P=.001) and emotional functioning (P<.001). Among all patients, PTS symptom severity was significantly associated with cognitive functioning (P<.001) and mental HRQoL (P=.01). Conclusions: Findings indicate that PTS symptoms after severe TBI are negatively associated with HRQoL and emotional, cognitive, and interpersonal functioning.