Background: Conflicting results are reported on the relationship between traumatic brain injury (TBI) and quality of life (QoL). In addition, very few studies have investigated the impact of TBI on QoL over time. The main goal of the present study was to evaluate the impact of TBI on QoL during the first five years following a road accident. Methods: A prospective cohort study was carried out with 957 road accident victims, aged ≥ 16 years and living in the Rhône administrative Département of France. The exposed group was composed of 222 participants who presented TBI with or without other injuries. The non-exposed group was composed of 735 subjects who suffered any other injuries without TBI. QoL was measured at 1, 3 and 5 years post-accident using the World Health Organization Quality of Life – brief questionnaire (WHOQOL-BREF). Results: TBI was associated with lower Overall QoL (β=-0.49, p=0.03) and Social Relationships scores (β=-0.46, p=0.01). Other factors were related to overall QoL: the occurrence of a further accident (β=-0.85, p=0.002) or new disease (β=-0.77, p<10-3) had negative impact, while regular sport activity before the accident (β=0.73, p<10-3) and return to work after the accident (β=1.48, p<10-3) were associated with better QoL. TBI did not influence the Physical, Psychological and Environment scores, while previous medical history was associated with lower scores in these domains. Conclusion: These results suggest that subjects with TBI had poorer Overall QoL during the first 5 years after the road accident. This impact was greatest in the Social relationships domain.