Hist2h2be (histone cluster 2, H2be) is expressed exclusively in olfactory chemosensory neurons. Expression is reduced by sensory activity, and it alters gene expression and promotes neuronal cell death in mature olfactory sensory neurons, potentially modulating olfactory neuronal population dynamics to adapt the olfactory repertoire to the environment. Endogenous Hist2h2be expression is knocked out and replaced by Gap43-mCherry in this targeted mutant strain. Red fluorescent protein is expressed in a pattern indistinguishable from that of Hist2h2be RNA. Homozygous knockout mice trained to discriminate between odors for a water reward learn the task more slowly and perform less efficiently than controls. Electro-olfactograms on main olfactory epithelium (MOEs) from H2be-knockout and heterozygous littermates revealed no obvious differences. Microarray analysis of whole MOE tissue in 6-month old H2be-knockout and wildtype mice revealed that approximately 6% of transcripts are differentially expressed. The categories enriched most strongly among up-regulated genes include `olfactory detection' (consisting of OR genes) and `RNA processing', and among downregulated genes include `developmental process' and `positive regulation of transcription'. OR expression differences between wildtype and H2be-knockout mice increase with age and display a significant bias towards up-regulation in the knockout. Analysis of active-CASP3-labeled mature olfactory neurons in H2be-KO and littermate controls revealed a 45% lower frequency of apoptosis in the mutant epithelium. Analysis of the life span of 5-bromo-2'-deoxyuridine (BrdU)-labeled neurons revealed a significantly higher survival rate in H2be-KO mice compared to controls. Comparison of MOE expression data obtained for wildtype and H2be-knockout mice revealed that for a subset of unilateral naris occlusion (UNO)-altered genes, including a large fraction of ORs, UNO-mediated changes are significantly attenuated in the MOE of the KO compared to the wildtype.