There is evidence that the first balloon inflation during coronary angioplasty provides a preconditioning stimulus leading to decreased ischemia during subsequent balloon inflations. Endogenous adenosine release may play a role in ischemic preconditioning. Therefore, intracoronary adenosine administration prior to the first balloon inflation during percutaneous transluminal coronary angioplasty (PTCA) might modify the preconditioning response to the first balloon inflation. Forty-one patients underwent double-blind randomization to treatment with 100 mcg of intracoronary adenosine or placebo prior to coronary angioplasty. Twenty patients (11 adenosine, 9 placebo) had complete resolution of ischemia between inflations allowing comparison between the first and second inflation. An angioplasty guidewire was used to obtain an intracoronary electrocardiogram. The mean reduction in ST elevation during the second inflation compared with the first was 4.8 mm in the placebo group and -0.8 in the adenosine group (p < 0.05 placebo vs. adenosine). Seven of 9 placebo patients had a decrease in ischemia during the second inflation compared with the first, while only 2 of 11 adenosine patients showed a reduction. It was concluded that (1) the first inflation during PTCA is a preconditioning stimulus leading to a decrease in ischemia during later inflations, and (2) intracoronary adenosine administration prior to PTCA modifies the preconditioning effect of the first inflation. These data suggest that adenosine plays a role in ischemic preconditioning in humans.