After an acute coronary occlusion that results in hemodynamic instability, the institution of percutaneous bypass (PB) can effectively support the failing myocardium. However, PB cannot augment coronary blood flow, and substantial regional myocardial necrosis can still occur. This experimental study was undertaken to determine whether combining PB with coronary venous retroperfusion using pressure-controlled intermittent coronary sinus occlusion (PICSO) would limit myocardial necrosis after an acute coronary occlusion. In 30 pigs, the second and third diagonal vessels were occluded with snares for 90 minutes followed by 30 minutes of cardioplegic arrest and 180 minutes of reperfusion with the snares released. During the period of coronary occlusion, 10 pigs were placed on PB, 10 pigs received PB+PICSO, and 10 pigs received no support (unmodified). Hearts treated with the combination of PB+PICSO had the highest wall motion scores (unmodified, 1.4 +/- 0.3; PB, 1.4 +/- 0.3; PB+PICSO, 2.8 +/- 0.3 [p < 0.05 versus unmodified and PB]) and the lowest area of necrosis in the area at risk (unmodified, 73% +/- 3%; PB, 43% +/- 2%; PB+PICSO, 14% +/- 2% [p < 0.05, PB and PB+PICSO versus unmodified; p < 0.05, PB+PICSO versus PB]). We conclude that combining PB with coronary venous retroperfusion significantly limits myocardial necrosis.