Chemokines are important regulators in the development, differentiation, and anatomic location of leukocytes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4+ T helper 1 (Th1) cells. We sought to determine the role of CCR5 in islet allograft rejection in a streptozotocin-induced diabetic mouse model. BALB/c islet allografts transplanted into CCR5−/− (C57BL/6) recipients survived significantly longer (mean survival time, 38 ± 8 days) compared with those transplanted into wild-type control mice (10 ± 2 days; P < 0.0001). Twenty percent of islet allografts in CCR5−/− animals without other treatment survived >90 days. In CCR5−/− mice, intragraft mRNA expression of interleukin-4 and -5 was increased, whereas that of interferon-γ was decreased, corresponding to a Th2 pattern of T-cell activation in the target tissues compared with a Th1 pattern observed in controls. A similar Th2 response pattern was also observed in the periphery (splenocytes responding to donor cells) by enzyme-linked immunosorbent spot assay. We conclude that CCR5 plays an important role in orchestrating the Th1 immune response leading to islet allograft rejection. Targeting this chemokine receptor, therefore, may provide a clinically useful strategy to prevent islet allograft rejection.