Well-tolerated protection against ischemia-reperfusion (IR) could benefit many patients. We tested the hypothesis that dipyridamole, an adenosine uptake inhibitor, provides such protection. Experiment 1: 10 healthy men were treated for 7 days in a double-blind randomised cross-over design with dipyridamole (2x200mg) and placebo (wash-out > 3 weeks). At the end of each treatment, volunteers performed 10 minutes forearm ischemic exercise. At reperfusion, 450 MBq 99m-Tc-annexin A5 was administered to measure IR injury. Gamma scans of both hands were acquired at 1 and 4 hours of reperfusion. Annexin targeting was defined as % difference in counts/pixel between IR and control thenar muscle. In 6 CABG patients, atrial tissue was harvested during surgery. Ex-vivo, in two trabecles, contractile force recovery was measured after 90 minutes of simulated ischemia. In each patient, one trabecle was exposed to dipyridamole (1 mg/l) while the other served as control. Dipyridamole significantly reduced annexin A5 targeting in those volunteers who received placebo first and dipyridamole next (from 27±14% and 30±16% (1 and 4 hours of reperfusion) to 15±9% and 16±10%), as opposed to those who received dipyridamole first and placebo next (from 17±13% and 19±6% to 20±14% and 19±6%; p=0.029 for interaction between treatment order and treatment effect). Atrial contractile recovery after IR was higher in dipyridamole compared to controls (43 ±10.1% and 19 ±3.2% resp.; p<0.05). Dipyridamole treatment protects against IR in forearm skeletal muscle of healthy volunteers (considering the wash-out period, this effect appears to persist >4 weeks) as well as in cardiac tissue from patients with coronary artery disease.