Islet transplantation is limited by suboptimal revascularization post-transplant. EPCs may have the potential to promote islet engraftment, to improve post transplant survival in vivo, but their mechanism of interaction with β-cells is unknown. C57B6 (B6) islets were isolated and density gradient purified. Bone marrow-derived EPCs were enriched by culture in defined medium and confirmed to express endothelial markers. The effects of co-transplantation of EPCs and islets were assessed in B6 diabetic mice (200mg/kg streptozotocin) using a marginal-mass of islets (200) transplanted under the kidney capsule. Islets were transplanted with or without d7 EPCs (1x106 cells). Blood glucose levels (BGL) were monitored for 28d (cure= two consecutive BGL<11.1mM). EPC co-transplant improved cure rate (83% at d14; n=12) compared to mice receiving islets alone (20%; n=10; p=0.002). The mechanism by which EPCs improved islet survival was investigated in vitro. Islets were cultured with EPC-conditioned medium and tested for glucose-stimulated insulin release. Secreted insulin was detected by ELISA and corrected for total protein. Stimulation indices (SI) were calculated. EPC-conditioned islets had an increased basal insulin release (0.7±0.22 ng/min/mg total protein; n=7) compared to controls (0.2±0.04 ng/min/mg; n=6; p<0.05). However, they had reduced ability to upregulate insulin release in high glucose conditions (SI = 1.3±0.5 compared to 4.2±0.9 for controls; p<0.05). Islets were also cultured above EPC monolayers in a non-contact assay. The effects on gene expression were analysed by quantitative real-time PCR (normalized to B2m). Co-cultured islets down-regulated the expression of Cx36 (0.4±0.05 fold relative to control islets; n=18; p<0.05). Conclusions: Islet and EPC co-transplantation improved the engraftment and survival of islets in vivo. This could be dependent to the modulation of Cx36 by EPCs, as seen in vitro. Thus may represent the adoption of a ‘survival’ islet phenotype where baseline insulin secretion is maintained during vascular remodeling – albeit in a dysregulated fashion.