Introduction Traumatic brain injury (TBI) is a major health problem. No single agent that can halt the progression of secondary injury exists. Progesterone, glutamine, ω3 fatty acids, and vitamin D 3 are all immune modulators, which can prevent secondary brain insult. Aim The aim of this study was to evaluate and compare the efficacy of progesterone alone with a half dose of progesterone plus vitamin D 3 , ω3 fatty acids, and glutamine (combination therapy) on the outcome of patients with acute TBI. Settings and design This was a randomized, prospective, controlled study. Patients and methods Sixty adult patients of both sexes, with moderate or severe TBI [Glasgow coma score (GCS) 4-12)] within 8 h of trauma, were equally randomly assigned to three groups: the control (C) group, which received the standard care and medications according to the guidelines of head trauma protocol; the progesterone (P) group, which received progesterone; and the combination therapy (T) group, which received a half dose of progesterone combined with vitamin D 3 , ω3 fatty acids, and glutamine. The GCS, ICU and hospital stay, computed tomography findings, mortality rate, and the Glasgow outcome scale (GOS) at 3 months after trauma were recorded and analyzed. Results Significant improvement in GCS and computed tomography findings, significantly shorter ICU and hospital stay, lower mortality rate, and more favorable GOS after 3 months were recorded among the therapeutic groups compared with the control group. Only ICU stay was significantly shorter on comparing the progesterone group with the T group. Conclusion Both progesterone and the combination therapy improved outcome in acute TBI, although progesterone dose was halved in the latter.