Tacrolimus (FK506) is a potent calcineurin inhibitor that is widely used for attenuation of immunoreaction in pancreatic islet transplantation. However, the continuous systemic administration of FK506 has been reported to result in patient non-compliance and associate with adverse side effects such as nephrotoxicity, neurotoxicity, and increment of cancer risk. To address these problems, in this study, poly(lactide-co-glycolide) (PLGA) microspheres were immobilized on the surface of pancreatic islets to locally deliver a very low dose of FK506 for effective inhibition of immune response in transplanted microenvironment while minimizing the presence of FK506 in other organs to reduce the side effects. Our results indicate that FK506-loaded PLGA microspheres (FK506/Ms) were successfully prepared by emulsion-evaporation method with the spherical morphology and size ranged from 3 to 10 µm. In addition, the polydopamine-functionalized microspheres were rapidly conjugated to the surface of islets without interfering with the viability and functionality of insulin-producing β-cells.  The encapsulating amount of FK506 in the coating layer was determined to be 581.6 ± 94.1 ng/400 IEQ/recipient. Moreover, immobilized microspheres were able to control the release of FK506 for approximately 40 days in a sustained manner. On day 14th post-transplantation, the concentration of FK506 in the transplanted area was maintained at approximately 2 ng/mg tissue while the drug was almost undetectable in the blood and other tissues. Interestingly, in a xenogeneic transplantation model, the median survival time (MST) of islets conjugated with FK506/Ms (MST: 31.63 ± 3.688 days) was significantly higher than MST of unmodified islets (MST: 12.2 ± 2.22 days) and MST of islets conjugated with blank microspheres (without drug) (MST: 11.714 ± 2.15 days) while no significant difference in survival rate was observed when a 10-fold higher dose of FK506 was daily injected.  In addition, the activation of T-cells in polydopamine-coated FK506/Ms conjugated islet recipients was significantly reduced as compared to unmodified islet recipients. The results suggest that the local controlled release of low-dose immunosuppressants could be a promising strategy to protect the pancreatic islets from host immune system while minimizing the adverse reactions.