INTRODUCTION: The prefrontal projections of the mediodorsal (MD) and central lateral (CL) thalamus have been implicated in the recovery of consciousness following severe traumatic brain injury (sTBI), but their specific roles are unknown. The CL has been proposed to modulate levels of arousal, while the MD modulates attention. METHODS: We generated tractograms in 25 patients with sTBI using DSI-Studio. The CL and MD were seeds and the orbitofrontal (OFC), dorsolateral prefrontal (dlPFC), medial prefrontal (mPFC), and anterior cingulate (ACC) cortices were targets. Fractional anisotropy (FA), a measure of tract integrity, and apparent diffusion coefficient (ADC), a proxy for neuronal injury, were computed for each tract and compared between the early (within 30 days post-injury) and late/no command followers. Spearman correlations were calculated between tract FA and ADC and final Glasgow Coma Scale (GCS) scores. RESULTS: Tractography revealed significantly increased MD-OFC tract FA in early compared late/no command followers (P = 0.0125). There was a statistically significant decrease in ADC in early compared late/no command followers in CL-dlPFC (P = 0.0281) and MD-dlPFC (P = 0.0454) tracts. GCS scores were significantly correlated with CL-ACC (P = 0.018) and CL-dlPFC (P = 0.0061) FA, and were not found to be significant in all MD tracts. CONCLUSIONS: The FA and ADC differences between early and late/no responders implicate tract integrity of the MD-OFC and dlPFC as key mediators in the return of command-following after TBI, respectively. The CL-ACC and CL-dlPFC tract FA were found to be associated with an increased final GCS score, which grades verbal, eye opening and motor responses. Our results corroborate the MD’s involvement in the content of consciousness, distinct from the CL’s in mediating the ascending arousal network.