Chronic inflammation exacerbates the cardiovascular complications of diabetes. Complement activation plays an important role in the inflammatory response and is known to be involved in ischemia/reperfusion (I/R) injury in the non-diabetic heart. The purpose of this study was to determine if increased complement deposition explains, in part, the increased severity of neutrophil-mediated I/R injury in the type 2 diabetic heart. Non-diabetic Zucker Lean Control (ZLC) and Zucker Diabetic Fatty (ZDF) rats underwent 30min of coronary artery occlusion followed by 120min of reperfusion. Another group of ZDF rats were treated with the complement inhibitor FUT-175 prior to reperfusion. Left ventricular (LV) tissue samples were stained for complement deposition and neutrophil accumulation following reperfusion. We found significantly more complement deposition in the ZDF LV compared to the ZLC (p<0.05) and complement deposition was associated with significantly greater neutrophil accumulation. In whole blood samples taken pre-ischemia and at 120min-reperfusion, neutrophils exhibited significantly more CD11b expression in the ZDF group compared to the ZLC group (p<0.05). Further, ICAM-1 expression following I/R was significantly increased in ZDF hearts compared to ZLC hearts (p<0.001). These results indicate that in the ZDF heart, increased ICAM-1 and PMN CD11b expression play a role in increasing PMN accumulation following I/R. The infarct size of the ZDF was significantly greater than ZLC (p<0.05) and treatment with FUT-175 significantly decreased infarct size, complement deposition, and PMN accumulation in the diabetic heart. These findings indicate an exacerbated inflammatory response in the type 2 diabetic heart which contributes to the increased tissue injury observed following ischemia and reperfusion.