The use of mouse blood as a model for human blood is often considered in the development of clinically relevant, gene expression-based disease biomarkers. However, the ability to derive biologically meaningful insights from microarray-based gene expression patterns in mouse whole blood, as in human whole blood, is hindered by high levels of globin mRNA. In order to characterize the effects of globin reduction on gene expression of peripheral mouse blood, we performed gene set enrichment analysis on genes identified as expressed in blood via microarray-based genome-wide transcriptome analysis. Depletion of globin mRNA enhanced the quality of microarray data as shown by improved gene expression detection and increased sensitivity. Compared to genes expressed in whole blood, genes detected as expressed in blood following globin reduction were enriched for low abundance transcripts implicated in many biological pathways, including development, g-protein signaling, and immune response. Broadly, globin reduction resulted in improved detection of expressed genes that serve as molecular binding proteins and enzymes in cellular metabolism, intracellular transport/localization, transcription, and translation, as well as genes that potentially could act as biomarkers for diseases such as schizophrenia. These significantly enriched pathways overlap considerably with those identified in globin-reduced human blood suggesting that globin-reduced mouse blood gene expression studies may be useful for identifying genes relevant to human disease. Overall, the results of this investigation provide a better understanding of the impact of reducing globin transcripts in mouse blood and highlight the potential of microarray-based, globin-reduced, mouse blood gene expression studies in biomarker development.