In patients with severe traumatic brain injury (TBI), a growth hormone deficiency (GHD) is frequent and may contribute to the cognitive sequelae and reduction in quality of life (QoL). Recent studies have suggested that GH replacement therapy (GHRT) can improve processing speed and memory. The aim of the study was to analyze the efficacy of GHRT on cognition, activities of daily living (ADL), and QoL and the factors that predicted and contributed to these effects. We included patients at least 1 year after their TBI and assessed pituitary functions (with stimulation tests), cognition (attention, memory, and executive function), participation in ADL and QoL. GHD was treated for at least 1 year in 23 patients, who were compared with 27 non-treated patients. Other deficiencies were also treated. Measurements were performed at baseline and 1 year later. An analysis of variance of the factors group and session (p ≤ 0.05) showed that most cognitive parameters had improved at 1 year (evidencing a session effect). A stronger effect of GHRT (i.e. a group x session interaction) was found for Rey Osterrieth complex figure recall and 2/6 domains in the QoL questionnaire ("personal" and "functional"). Trends (p ≤ 0.07) were also found for spatial orientation and immediate recall in the verbal memory test. Greatest improvements were associated with lower performance before treatment. The magnitude of the improvements in ADL and QoL was moderately correlated with the improvement in cognition. In conclusion, replacement therapy can improve cognition and QoL in patients with TBI who have GHD, especially in those with severe disabilities.