—Ischemia induces both hypoxia and inflammation that trigger angiogenesis. The inflammatory reaction is modulated by production of anti-inflammatory cytokines. This study examined the potential role of a major anti-inflammatory cytokine, interleukin (IL)–10, on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by artery femoral occlusion in both C57BL/6J IL-10^+/+ and IL-10^–/– mice. After 28 days, angiogenesis was quantified by microangiography, capillary, and arteriole density measurement and laser Doppler perfusion imaging. The protein levels of IL-10 and vascular endothelial growth factor (VEGF) were determined by Western blot analysis in hindlimbs. IL-10 was markedly expressed in the ischemic hindlimb of IL-10^+/+ mice. Angiogenesis in the ischemic hindlimb was significantly increased in IL-10^–/– compared with IL-10^+/+ mice. Indeed, angiographic data showed that vessel density in the ischemic leg was 10.2±0.1% and 5.7±0.4% in IL-10^–/– and IL-10^+/+ mice, respectively (P<0.01). This corresponded to improved ischemic/nonischemic leg perfusion ratio by 1.4-fold in IL-10^–/– mice compared with IL-10^+/+ mice (0.87±0.05 versus 0.63±0.01, respectively; P<0.01). Revascularization was associated with a 1.8-fold increase in tissue VEGF protein level in IL-10^–/– mice compared with IL-10^+/+ mice (P<0.01). In vivo electrotransfer of murine IL-10 cDNA in IL-10^–/– mice significantly inhibited both the angiogenic process and the rise in VEGF protein level observed in IL-10^–/– mice. No changes in vessel density or VEGF content were observed in the nonischemic hindlimb. These findings underscore the antiangiogenic effect of IL-10 associated with the downregulation of VEGF expression and suggest a role for the inflammatory balance in the modulation of ischemia-induced angiogenesis.