OBJECTIVES: To compare markers of inflammation after transfusion of leukoreduced (LR) packed RBCs (pRBCs) versus non-LR pRBCs in dogs with critical illness requiring blood transfusion, and to report survival to discharge and rates of transfusion reactions in these dogs. DESIGN: Prospective randomized blinded clinical study June 2014-September 2015. SETTING: University veterinary teaching hospital. ANIMALS: Twenty-three client-owned critically ill dogs, consecutively enrolled. INTERVENTIONS: Dogs requiring a single pRBC transfusion were randomized into the LR or non-LR pRBC group. Exclusion criteria included: requirement for multiple blood products, history of previous blood transfusion, and administration of anti-inflammatory or immunosuppressive medication prior to enrollment. MEASUREMENTS: Blood samples were obtained immediately prior to transfusion, then 2 and 24 hours following transfusion. Parameters measured at each time point included: PCV, WBC count, segmented and band neutrophil counts, fibrinogen, and plasma lactate and C-reactive protein concentrations. Acute patient physiologic and laboratory evaluation fast score was calculated on admission. RESULTS: Eleven dogs were included in the LR group and 12 in the non-LR group; scores of illness severity were not significantly different between groups. Total WBC count was significantly higher in the non-LR versus LR group 24 hours following pRBC transfusion, but this difference was not evident 2 hours following transfusion. No other inflammatory parameters at any time point were significantly different between LR versus non-LR pRBC transfused dogs. Survival rates to discharge for LR and non-LR groups were 8/11 and 9/12, respectively. Acute transfusion reactions were identified in 1/11 and 2/12 dogs in the LR and non-LR group, respectively. All transfused blood was stored ≤12 days. CONCLUSIONS: Most markers of inflammation did not significantly increase following transfusion of LR versus non-LR pRBCs stored ≤12 days in ill dogs. Further prospective, randomized trials are needed in clinically ill dogs to determine the benefit of prestorage leukoreduction.