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Objective: To investigate the impact of the number of drugs on rehabilitation outcomes for patients with acute traumatic brain injury. Design: Retrospective cohort study. Setting: Hospital‐based database created by the Japan Medical Data Center. Participants: Patients with acute traumatic brain injury admitted between April 2014 and November 2017. Methods: Analysis of relationships among 1‐5 and ≥ 6 drugs as well as clinical outcomes in 2603 patients. Main Outcome Measurements: The primary outcome was defined as the Barthel index efficiency, and the secondary outcome was Barthel index gain and length of hospital stay. Results: Median Barthel index score on admission was 40. Barthel index efficiency and Barthel index gain were significantly higher in the group that had taken 1‐5 drugs than in the group that had taken ≥6 drugs on admission (median: 1.19 vs 0.50, 20.0 vs 10.0). Also, the group that had taken 1‐5 drugs had a significantly shorter length of hospital stay than in the group that had taken ≥6 drugs on admission (median 11.0 vs 14.0). Moreover, multiple linear regression analysis showed that having taken ≥6 drugs on admission was independently associated with Barthel index efficiency, Barthel index gain, and length of stay. Conclusions: Taking≥6 drugs for acute traumatic brain injury was associated with lower Barthel index efficiency, lower Barthel index gain, and longer length of stay than taking 1‐5 drugs. [ABSTRACT FROM AUTHOR]