New serotonin reuptake inhibitors are available for the treatment of affective disorders and sleep dysfunction in traumatic brain injury (TBI) patients. Commonly reported serotonergic side-effects include nausea, headache, dizziness, nervousness and orthostatic hypotension. Trazodone, a non-selective serotonin reuptake inhibitor, is often used in conjunction with fluoxetine, a selective serotonin reuptake inhibitor, in order to combat the insomnia associated with fluoxetine. Successful use of this combination is generally limited by the cumulative serotonergic side-effects of the two medications. This paper describes the first reported case of speech dysfunction as a complication of combined trazodone and fluoxetine use. A 43-year-old male suffered bilateral wrist fractures and a moderate TBI during a fall. Within 1 week of adding fluoxetine to trazodone the patient developed new-onset dysarthria and speech blocking. Upon discontinuation of fluoxetine, speech returned to normal. Possible mechanisms include inhibition of hepatic metabolism, unmasking of caudate nucleus injury, increased noradrenergic activity or previously unreported serotonergic effects. This case illustrates the importance of monitoring drug combinations for unexpected side-effects in the TBI population.