We designed this experimental study to determine the optimal cycle for intermittent inflow occlusion during liver resection. A cycle of intermittent clamping (IC) for 15 minutes of ischemia followed by reperfusion for 5 minutes during liver resection is currently the most popular protocol used by experienced liver centers. As each period of reperfusion is associated with bleeding, longer periods of clamping would be advantageous. However, the longest safe duration of successive ischemia is unknown. Three groups of mice were subjected to a total liver ischemic period for 90 minutes; 2 groups underwent IC for 15 or 30 minutes, respectively, followed by 5 minutes of reperfusion, while the control group was subjected to continuous inflow occlusion only. The degree of tissue injury was assessed using biochemical and histological markers, as well as animal survival. While serious injury was observed in the continuous clamping group, both IC groups were associated with minimal injury, including lesser degrees of apoptosis and necrosis. All animals survived in the IC groups, while all animals died following 90 minutes of continuous inflow occlusion. In conclusion, intermittent portal pedicle clamping with 15- or 30-minute cycles is highly protective. A period of 30 minutes clamping should be preferred, since this would decrease the amount of blood loss associated with each cycle. This data should be confirmed in humans, and may represent a change in the current practice of hepatic surgery.