The aim of this study was to investigate the differences in the gene expression profiles of radiation-sensitive (RS) and radiation-resistant (RR) sinonasal squamous cell carcinoma (SNSCC) and to identify prognostic markers for the radiation reaction of SNSCC. We first examined the differentially expressed genes (DEGs) in RS and RR SNSCC tissues by analyzing clinical samples with GeneChip Human Transcriptome Array 2.0 (HTA 2.0).To understand the functional significance of the molecular changes, we examined the DEGs with Gene Ontology (GO) and pathway analyses to identify the core genes. The expression of several core genes (CCND2, COL5A2, GADD45B, and THBS2) was confirmed with reverse transcription quantitative PCR (RT-qPCR) in a larger series of tissues. We identified 208 DEGs, of which 76 were upregulated and 132 downregulated in the RS tissues relative to the RR tissues. The DEGs were mainly involved in the regulation of cell proliferation, the NF-kappaB signaling pathway, the cell adhesion molecule signaling pathway, and the extracellular matrix-receptor interaction signaling pathway. RT-qPCR confirmed that the CCND2, COL5A2, GADD45B, and THBS2 genes were significantly differentially expressed in the RS and RR tissues, consistent with the GeneChip data. These results extend our understanding of the molecular mechanisms underlying the sensitivity of SNSCC to radiation. The DEGs are involved in the differential response to radiation therapy and the dysregulated core genes identified in this study can be used to predict radiation sensitivity in SNSCC.