Objective: To evaluate the course of mood and identify its determinants up to 3 years after moderate to severe traumatic brain injury (TBI). Design: Prospective cohort study. Patients: Patients hospitalised with moderate to severe TBI, who survived until hospital discharge. Methods: At 3, 6, 12, 18, 24, and 36 months post-injury, mood was assessed with the Wimbledon Self-Report Scale (WSRS) in the home environment. Motor and cognitive outcome were assessed with the Functional Independence Measure (FIM), and the Functional Assessment Measure (FAM), respectively. Repeated measurements analysis was performed to determine the course of mood over time and its determinants. Results: A total of 98 patients (72% men), aged 33 (SD 12.9) years, 78% with severe TBI, was included. Mood did not change until 18 months post TBI, after which it significantly improved (p = 0.016). The FIM score significantly improved up to 18 months post-TBI (p = 0.012) and the FAM score up to 12 months post-TBI (p = 0.000), after which both remained stable. In univariable analyses, time post TBI (β = -0.04, p = 0.008), initial discharge destination (β = 2.13, p = 0.010), FIM (β = -0.22, p<0.001) and FAM (β = -0.29, p<0.001) were significant predictors of mood. In a multivariable mixed model, time post TBI, FAM score, and discharge destination were the strongest predictors of mood. Higher FAM scores were related to better mood scores (β = -0.28, p<0.001). Patients initially discharged home tended to have better mood scores over time than patients first treated in inpatient rehabilitation centers or nursing homes (β = 1.27; p = 0.071). Conclusion: Mood starts to improve 18 months after TBI when motor and cognitive outcome have stabilized. Time post TBI, cognitive outcome and initial discharge destination are the strongest predictors of mood up to 3 years after TBI. These data suggest that mood scores of patients with moderate and severe TBI should be frequently monitored, especially in rehabilitation centers and nursing homes.