Psychostimulants that affect neurotransmitters implicated in cognitive function and neural plasticity have potential to enhance the rate and extent of recovery after traumatic brain injury (TBI). Ten milligrams dextroamphetamine (DEX) or an identical placebo was administered daily for 3 weeks to 32 participants with moderate to severe TBI, engaged in inpatient rehabilitation, at a mean of 2 months post injury. A variety of outcome measures assessing cognitive function and overall functional status was administered at weekly intervals, to examine effect sizes that may inform a larger trial, and to evaluate safety. Results indicated trivial-to-small effect sizes for DEX-placebo differences, with the largest effects seen on speed of information processing (more improvement with DEX) and agitation (exacerbation with DEX). Examination of adverse events and vital signs suggested safety of DEX, but the pattern of results did not suggest accelerated recovery due to the drug. Future trials of DEX in this population need to consider the impact of floor effects of commonly used measures of cognitive and physical function, and the heterogeneity of TBI. Although the small sample precludes definitive conclusions, these findings are not encouraging with regard to clinical trials of DEX in subacute TBI.