Insulin producing β-cells are exposed to hypoxic stress in the early period after islet transplantation. Although it has been suggested that hypoxia leads to islet loss, the underlying mechanisms are unclear. In this study, the early transcriptional profiles of b cell response to hypoxia were determined by using the Affymetrix Murine Genome Array U74Av2 GeneChip (about 12,422 genes). In addition to the upregulation of genes associated with glycolysis, genes related to apoptosis and stress response were also upregulated. The downregulated genes on hypoxia are classified as transcription and inflammatory response. These findings were confirmed by TUNEL assay and real-time reverse transcription-PCR for mRNA of genes related to apoptosis. On the other hand, we have found that the transcription factor NFκB was activated by hypoxia in islet cells. The affected genes involved in the activated NFκB pathway were mainly categorized as apoptosis-related genes by quantitative real-time PCR array (84 genes). Our comprehensive analysis of transcriptional changes of islets by hypoxia may assist the development of strategies that protect islet grafts from early loss.