BACKGROUND Despite the proven efficacy of pressure-controlled intermittent coronary sinus obstruction (PICSO) and synchronized retrograde perfusion (SRP) in salvaging ischemic myocardium, wide application of these coronary sinus (CS) retroperfusion techniques has been limited by concerns about their safety and complexity and in particular the need for repeated occlusion of the CS with a balloon. To address these concerns a simplified retroperfusion technique (SR) was developed that continuously infuses superior vena caval blood at 7 mL/min into the CS catheter without balloon occlusion. METHODS Thirty pigs underwent 90 minutes of ischemia imposed by snaring the two largest diagonal branches of the left anterior descending artery and were randomized to one of five treatment groups: One group received no retroperfusion (control). Three groups had immediate (Im) institution of PICSO, SRP, or SR. In a final group, an initial 60 minutes of ischemia was followed by 30 minutes of delayed SR with superior vena caval blood. All animals were then placed on cardiopulmonary bypass and, after a 60-minute cardioplegic arrest, the coronary artery obstructions were removed, to simulate surgical revascularization. This was followed by 3 hours of reperfusion. The area of myocardium at risk and the area of infarction were determined by methylene blue and triphenyltetrazolium chloride staining with planimetric quantification. RESULTS Results are reported as mean +/- standard deviation. The area of the left ventricle at risk for infarction was similar in all the treatment groups and represented 22.3% +/- 4.1% of the left ventricular mass. The area of infarction after 3 hours of reperfusion was 48.5% +/- 11.0% for the control group, 26.8% +/- 7.3% for Im-PICSO, 24.9% +/- 4.8% for Im-SRP, 22.4% +/- 6.6% for Im-SR, and 27.7% +/- 7.2% for delayed SR (p < 0.01 for each group versus control). The mean CS pressure (in mm Hg) during treatment was 6.3 +/- 1.7 for the control group, 25.7 +/- 4.5 for Im-PICSO, 22.8 +/- 3.7 for Im-SRP, 5.0 +/- 1.5 for Im-SR, and 6.3 +/- 2.1 for delayed SR (p < 0.01 for Im-PICSO and Im-SRP versus control). CONCLUSIONS The simplified retroperfusion technique is as effective as PICSO and SRP in salvaging ischemic myocardium, but is considerably simpler. The simplified retroperfusion technique is inherently safer because of the lower CS pressures imposed by low flows and the lack of CS balloon obstruction. The efficacy of delayed SR has profound implications on possible mechanisms of ischemic myocardial salvage. Further investigation is warranted.