Objective: To establish whether or not the serotonin reuptake inhibitor (SSRI) sertraline can improve arousal and alertness of patients with traumatic brain injury (TBI) and associated diffuse axonal injury (DAI). Serotonin is a major inhibitory as well an excitatory neurotransmitter, and serotonergic neurons modulate the activity of brain regions responsible for motor control, arousal, attention, and emotional regulation. Setting: Tertiary care inpatient rehabilitation centre directly attached to a university hospital level-one trauma centre. Design: Prospective placebo-controlled randomized trial utilizing sertraline on admission to acute rehabilitation. Data set: Eleven subjects, post-high speed motor vehicle crash and post-severe TBI (GCS<8) with presumed DAI randomized to receive either sertraline 100 mg per day or placebo for 2 weeks. All subjects were within 2 weeks of acute injury. Outcome measures recorded were the Orientation Log (daily), Agitated Behaviour Scale (daily), and the Galveston Orientation and Amnesia Test (weekly). Results: Both placebo and active medication groups demonstrated similar rates of improvement on all three scales. There was no difference in the rates of recovery for either study group (p > 0.05, ANOVA with repeated measures). The groups did not demonstrate a statistically significant negative effect on recovery either, although the size is too small for a statistically reliable beta-effect. Conclusion: This pilot fails to establish whether the early use of sertraline may improve alertness, decrease agitation or improve cognitive recall of material. This may be due to the small size of the study group, the brief duration of treatment or by a skewed placebo group. Larger studies will be required to prove any efficacy. There were no complications with its use and sertraline did not demonstrate a detrimental effect on recovery. This indicates that sertraline may be safe to use in the treatment of psychiatric or behavioural complications attributable to TBI.