Background: It is not known which patient subgroups may benefit most from off-pump coronary artery bypass grafting (OPCAB) rather than coronary artery bypass grafting on cardiopulmonary bypass (CPB). Methods: The Society of Thoracic Surgeons database was queried for all isolated, primary coronary artery bypass graft cases between January 1, 1997, and December 31, 2007, at a US academic center. The Society of Thoracic Surgeons Predicted Risk of Mortality (PROM) was calculated by a formula based on 30 preoperative risk factors. It was used in three ways to compare 30-day operative mortality between patients treated with OPCAB versus CPB. First, patients were divided into quartiles based on their PROM, and mortality rates were compared between OPCAB and CPB patients within each PROM quartile. Second, a logistic regression model tested for an interaction between surgery type and PROM; a significant interaction would indicate that the relative mortality risk of OPCAB versus CPB varied with different PROM levels. Finally, locally smoothed kernel regression curves were used to visually estimate a threshold PROM point at which mortality rates diverge for the surgery types. Results: There were 14,766 consecutive patients, 7,083 OPCAB (48.0%) and 7,683 CPB (52.0%). There was no difference in operative mortality between OPCAB and CPB for patients in the lower two risk quartiles. In the higher risk quartiles there was a mortality benefit for OPCAB (odds ratio, 0.62 and 0.45 for OPCAB in the third and fourth risk quartiles). Logistic regression analysis confirmed a significant interaction between surgery type and PROM (p = 0.005) meaning that OPCAB is especially beneficial to patients with higher PROM. This benefit is most significant for patients with PROM values above 2.5% to 3%, where mortality curves sharply diverge. Conclusions: Off-pump coronary artery bypass grafting is associated with lower operative mortality than coronary artery bypass grafting on CPB for higher risk patients. This mortality benefit increases with increasing PROM.