The role of the beta 2AR (beta 2 adrenergic receptor) after stroke is unclear as pharmacological manipulations of the beta 2AR have produced contradictory results. We previously showed that mice deficient in the beta 2AR (beta 2KO) had smaller infarcts compared with WT (wild-type) mice (FVB) after MCAO (middle cerebral artery occlusion), a model of stroke. To elucidate mechanisms of this neuroprotection, we evaluated changes in gene expression using microarrays comparing differences before and after MCAO, and differences between genotypes. Genes associated with inflammation and cell deaths were enriched after MCAO in both genotypes, and we identified several genes not previously shown to increase following ischaemia (Ccl9, Gem and Prg4). In addition to networks that were similar between genotypes, one network with a central core of GPCR (G-protein-coupled receptor) and including biological functions such as carbohydrate metabolism, small molecule biochemistry and inflammation was identified in FVB mice but not in beta 2KO mice. Analysis of differences between genotypes revealed 11 genes differentially expressed by genotype both before and after ischaemia. We demonstrate greater Glo1 protein levels and lower Pmaip/Noxa mRNA levels in beta 2KO mice in both sham and MCAO conditions. As both genes are implicated in NF kappa B (nuclear factor kappa B) signalling, we measured p65 activity and TNF alpha (tumour necrosis factor alpha) levels 24 h after MCAO. MCAO-induced p65 activation and post-ischaemic TNF alpha production were both greater in FVB compared with beta 2KO mice. These results suggest that loss of beta 2AR signalling results in a neuroprotective phenotype in part due to decreased NF-kappa B signalling, decreased inflammation and decreased apoptotic signalling in the brain.