Apolipoprotein E (ApoE), a cholesterol transporter and an immunomodulator, is brain protective after experimental stroke and implicated in brain repair. Here, we study the involvement of ApoE in the restoration of brain function after experimental stroke, by using animal housing conditions that differentially improve recovery after occlusion of the middle cerebral artery occlusion (MCAO). We found that after MCAO the ApoE levels increased in the injured hemisphere over a 30 days recovery period. The exception was a proximal narrow peri-infarct rim, in which ApoE was solely localized in S100 β+/glial fibrillary acidic protein (GFAP) negative reactive astrocytes at 4 to 7 days of recovery. Enriched housing after MCAO caused a marked decrease in ApoE levels compared with standard housing conditions, particularly in the ApoE/S100 β+ reactive astrocytes. In addition, the levels of interleukin 1 β were lower in animals housed in an enriched environment. We propose that during the subacute phase after experimental stroke a zone for tissue reorganization with low cellular ApoE levels is formed. We conclude that the strong sensori-motor stimulation provided by enriched housing conditions mitigates the inflammatory response after stroke decreasing the level of ApoE that may contribute to the observed improvement of functional recovery.