OBJECTIVE: To investigate the relationship of post-concussive complaints, anxiety and depression with vocational outcome in patients with traumatic brain injury (TBI) of various severity and to assess sex differences. DESIGN: A prospective cross-sectional cohort study. SETTING: Level I trauma center. PARTICIPANTS: Adults (n=242) with TBI of various severity. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Extended Glasgow Outcome Scale (GOS-E), Return to Work (RTW), Head Injury Symptom Checklist (HISC), Hospital Anxiety and Depression Scale (HADS). RESULTS: In 67% of patients complaints were present, and 22% were anxious and 18% depressed. Frequency of complaints increased significantly with injury severity, in contrast to anxiety and depression. Frequencies of patients with anxiety and depression (9 and 5%) were lower with complete RTW than with incomplete RTW (42% and 37%; P<0.001). Patients with minor TBI with complaints were more anxious (50% vs. 27%; P<0.05) and depressed (46% vs. 23%; P<0.05) compared to other severity categories, also for patients with incomplete RTW (67% vs. 36% and 60% vs. 30% respectively). A higher percentage of women with minor TBI was depressed (45% vs. 13%; P=0.01) and had incomplete RTW (50% vs. 18%; P<0.05) compared to men. Multiple regression analysis showed injury severity, complaints, anxiety and depression all predictive of RTW (explained variance 45%). In all severity categories, anxiety and depression were predictive of RTW, complaints and sex only for minor TBI. CONCLUSIONS: Anxiety and depression are related to vocational outcome after TBI, with a different profile in the minor TBI category, partly due to sex differences.