Background Phenoxybenzamine effectively reduces radial artery (RA) spasm in vitro, but clinical data supporting its use during coronary revascularization are lacking. Therefore, the purpose of this study was to evaluate the clinical safety and efficacy of RA treatment with phenoxybenzamine. Methods Data were collected prospectively on 698 patients who underwent coronary artery bypass grafting with a RA between 1997 and 2005. Of these, 311 patients received RA grafts incubated in 2 mg/mL phenoxybenzamine for 15 minutes, and 387 patients received RA grafts treated with verapamil and nitroglycerin (VG solution). Demographic, operative, and postoperative data were compared retrospectively using multivariate regression techniques. Results The incidence of perioperative myocardial events (defined as either low cardiac output syndrome or perioperative myocardial infarction) was significantly reduced in the phenoxybenzamine group (6.8% vs 11.9%, phenoxybenzamine vs VG solution; p = 0.03). Perioperative myocardial enzyme release, as measured by postoperative maximum creatine kinase, was also reduced in the phenoxybenzamine group (743.0 ± 677.9 vs 937.2 ± 1236.8 U/L, phenoxybenzamine vs VG solution; p = 0.014). After adjusting for patient and procedural factors, the use of phenoxybenzamine was independently associated with reductions in peak creatine kinase (by −343.0 ± 136.7 U/L; p = 0.012) and peak troponin T level (by −0.50 ± 0.19 ng/mL; p = 0.010). No differences in vasopressor support, length of stay, or other complications were observed. Conclusions Treatment of RA grafts with phenoxybenzamine was associated with a reduction in perioperative myocardial injury and adverse cardiac events in this study population. Investigations to further evaluate the potential benefits of phenoxybenzamine in randomized settings are warranted.