Abstract Background We previously showed that intermittent cross clamping with fibrillation affords myocardial protection equivalent to cardioplegic arrest. In this study, we examined whether cariporide (Aventis Pharma, Frankfurt, Germany), a specific sodium-hydrogen exchanger inhibitor, enhanced the protective effect of intermittent cross-clamp fibrillation (ICCF). Methods Isolated rat hearts were Langendorff-perfused (20 mins) with bicarbonate buffer and function (left ventricular developed pressure) measured. In each of three separate protocols that incorporated progressively longer ischemic durations, hearts were randomly allocated to one of three groups: group 1 was the control group with 40, 60, or 80 minutes of continuous global ischemia. Group 2 was the ICCF group with 4, 6, or 8 cycles of 10 minutes ICCF and 10 minutes of reperfusion in sinus rhythm. Group 3 was the ICCF plus cariporide group, which was the same as group 2, but also with 3 μmoles/L cariporide present in perfusate from 10 minutes before the ICCF cycles. Hearts were reperfused for 60 minutes with drug-free buffer and recovery (percentage of initial function) was measured. Hearts were maintained at 37°C throughout the protocols. In protocol 3 (80 minutes ischemia per 8 cycles of ICCF), creatine kinase leakage (myocardial injury) and triphenyl tetrazolium chloride staining (myocardial viability) were also measured. Protocols 1, 2, and 3 had n = 8 hearts, n = 6 hearts, and n = 6 hearts in each group, respectively. Results In the three protocols, the recoveries of left ventricular developed pressure in the control group, the ICCF group, and the ICCF plus cariporide group, respectively, for protocol 1 were: 26% ± 3%, 70% ± 2% ( p < 0.05 vs the control group) and 74% ± 2% ( p < 0.05 vs the control group), respectively. For protocol 2 these were: 16% ± 2%, 55% ± 1% ( p < 0.05 vs the control group), and 70% ± 3% ( p < 0.05 vs the control and ICCF groups), respectively. For protocol 3 these were: 8% ± 2%, 41% ± 3% ( p < 0.05 vs the control group), and 63% ± 2% ( p < 0.05 vs the control and ICCF groups), respectively. Recovery of left ventricular end-diastolic pressure mirrored that of left ventricular developed pressure in all protocols. In protocol 3, total creatine kinase leakage (international units per gram wet weight) was 88 ± 12, 47 ± 4 ( p < 0.05 vs the control group), and 17 ± 1 ( p < 0.05 vs the control and ICCF groups), respectively, and triphenyl tetrazolium chloride staining (arbitrary units per gram wet weight) was 0.17 ± 0.04 in the control group, 0.39 ± 0.04 ( p < 0.05 vs the control group) in the ICCF group, and 0.47 ± 0.08 ( p < 0.05 vs the control group) in the ICCF plus cariporide group, respectively. Conclusions Sodium-hydrogen exchanger inhibition with cariporide enhances the myocardial protection afforded by ICCF, with the additive benefit becoming more apparent with increasing severity of the ischemic insult. Sodium-hydrogen exchanger inhibition may provide a significant protective reserve during ICCF, particularly when longer procedures are required.