Aims/Hypothesis: Ischemic preconditioning (IPC), cyclical bouts of non-lethal ischemia, provides immediate protection against ischemic injury, which is evident both locally and remotely. Given the similarities in protective effects of exercise with ischemic preconditioning, we examined whether handgrip exercise also offers protection against endothelial ischemia-reperfusion (IR)-injury, and whether this protection is equally present in the local (exercised) and remote (contralateral, non-exercised) arm. Methods: Fifteen healthy males (age 24±3 years; BMI 25±2 kg/m2) attended the laboratory on 3 occasions. Bilateral brachial artery flow-mediated dilation (FMD) was examined at rest and following a temporary IR-injury in the upper arm. Prior to the IR-injury, in the dominant (local) arm participants performed (randomised, counterbalanced); i. 4x5 minutes unilateral handgrip exercise (50% maximal voluntary contraction), ii. 4x5 minutes unilateral IPC (220 mmHg), or iii. 4x5 minutes rest (control). Data were analysed using repeated measures general linear models. Results: Allometrically scaled FMD declined after IR in the control condition (4.6 ± 1.3% to 2.2 ± 1.7%, P<0.001), as well as following handgrip exercise (4.6 ± 1.6% to 3.4 ± 1.9%, P=0.01), however was significantly attenuated with IPC (4.5 ± 1.4% to 3.8 ± 3.5%, P=0.14). There were no differences between the local and remote arm. Conclusion: Our findings reinforce the established protective effects of IPC in young, healthy males, and also highlight a novel strategy to protect against IR injury with handgrip exercise, which warrants further study