This study was designed to determine whether exposure to multimodal early onset stimulation (MEOS) combined with environmental enrichment (EE) after traumatic brain injury (TBI) would improve neurological recovery and to elucidate its morphological correlates. Male Sprague-Dawley rats were subjected to lateral fluid percussion (LFP) brain injury or to sham operation. After LFP, one-third of the animals (injured and sham) were placed under conditions of standard housing (SH), one-third were kept in EE only, and one-third received EE + MEOS. Assessment of neuromotor function 24 h post-injury using a standardized composite neuroscore test revealed an identical pattern of neurological impairment in all animals subjected to LFP. Neuromotor dysfunction in SH animals remained on a similar level throughout the experiment, while improvements were noted in both other groups 7 days post-injury (dpi). On 15 dpi, reversal of neuromotor dysfunction was significantly better in EE + MEOS animals vs. SH- and EE-only groups. In parallel, the comparison of lesion volume in EE + MEOS- vs. EE-only vs. SH rats revealed that animals exposed to EE + MEOS had consistently the lowest values (mm3, mean +/- SD; n = 6 rats in each group) as measured in serial brain sections immunostained for neuron-specific enolase (5.2 +/- 3.4 < or = 5.5 +/- 4.1 < 9.5 +/- 1.9), caspase 3-active/C3A (5.9 +/- 4.0 < or = 6.4 +/- 3.9 < 10.3 +/- 1.8) and glial fibrillary acidic protein (6.0 +/- 3.4 < or = 6.5 +/- 4.3 < 10.7 +/- 1.2). This first report on the effect of EE + MEOS treatment strongly indicates that the combined exposure reduces CNS scar formation and reverses neuromotor deficits after TBI in rats.