Background Our aim was to investigate the effects of ischemic preconditioning on infarct size and regional myocardial blood flow in ketamine-xylazine anesthetized rabbits. Methods Rabbits were randomly assigned to preconditioning (two 5-minute coronary artery occlusions, each followed by 5 minutes of reperfusion) or to control (20-minute waiting period) treatment, both of which were followed by sustained occlusion and reperfusion. Regional myocardial blood flow was measured late during occlusion and after 3 hours of reperfusion. In a second study, regional myocardial blood flow was measured during a preconditioning occlusion (in preconditioned hearts) and early and late during the sustained occlusion. Results Infarct size was significantly reduced in preconditioned hearts (30% ± 5% area at risk vs 53% ± 5% in controls, P< 0.005). Tissue salvage occurred in both subepicardium and subendocardiurn of both groups; however, preconditioning markedly improved salvage in all myocardial layers compared with controls. Preconditioning altered regional myocardial blood flow during both late occlusion and reperfusion. After 3 hours of reperfusion, flow to the previously ischemic myocardium was significantly higher in the preconditioned group (0.91 ± 0.11 vs 0.61 ± 0.09 mL/min/g, P< 0.05). Data from the second study indicated that preconditioning did not alter blood flow during early occlusion. Conclusions These results indicate that preconditioning reduces infarct size in the ketamine-xylazine anesthetized rabbit. Preconditioning does not alter blood flow during early occlusion, and the enhanced blood flow observed in the ischemic region of preconditioned hearts late in occlusion is probably secondary to infarct size reduction. In addition, after reperfusion, flow to the previously ischemic myocardium was significantly higher in preconditioned hearts, suggesting improved reflow in this region.