CX3CR1 (fractalkine receptor) is important for sustaining normal microglial activity in the brain. Lack of CX3CR1 reportedly results in neurotoxic microglial phenotype in disease models. The objective of this study was to test the hypothesis that the absence of CX3CR1 worsens the outcome in cerebral ischemia. We observed significantly smaller (56%) infarcts and blood—brain barrier damage in CX3CR1-deficient (CX3CR1−/−) animals compared with CX3CR1 +/− and wild-type mice after transient occlusion of the middle cerebral artery (MCAo). Functional recovery of CX3CR1−/−animals was enhanced, while less number of apoptotic cells and infiltrating leukocytes were found in the ipsilateral hemisphere. Expression of IL-1β mRNA, protein, and interleukin (IL)-1Ra and tumor necrosis factor (TNF)-α mRNAs was lower in CX3CR1−/− mice, whereas no difference was observed in the number of IL-1β-expressing microglia or plasma IL-1β concentration. We observed early IL-1β expression in astrocytes in vivo after MCAo and after oxygen—glucose deprivation in vitro, which might contribute to the ischemic damage. Our findings indicate that lack of CX3CR1 does not result in microglial neurotoxicity after MCAo, but rather significantly reduces ischemic damage and inflammation. Reduced IL-1β and TNFα expression as well as decreased leukocyte infiltration might be involved in the development of smaller infarcts in CX3CR1−/− animals.