The effectiveness of perioperative β-blockade in patients undergoing noncardiac surgery remains controversial. To determine the associations of early perioperative exposure to β-blockers with 30-day postoperative outcome in patients undergoing noncardiac surgery. A retrospective cohort analysis evaluating exposure to β-blockers on the day of or following major noncardiac surgery among a population-based sample of 136,745 patients who were 1:1 matched on propensity scores (37,805 matched pairs) treated at 104 VA medical centers from January 2005 through August 2010. All cause 30-day mortality and cardiac morbidity (cardiac arrest or Q-wave myocardial infarction). Overall 55,138 patients (40.3%) were exposed to β-blockers. Exposure was higher in the 66.7% of 13,863 patients undergoing vascular surgery (95% CI, 65.9%-67.5%) than in the 37.4% of 122,882 patients undergoing nonvascular surgery (95% CI, 37.1%-37.6%; P < .001). Exposure increased as Revised Cardiac Risk Index factors increased, with 25.3% (95% CI, 24.9%-25.6%) of those with no risk vs 71.3% (95% CI, 69.5%-73.2%) of those with 4 risk factors or more exposed to β-blockers (P < .001). Death occurred among 1.1% (95% CI, 1.1%-1.2%) and cardiac morbidity occurred among 0.9% (95% CI, 0.8%-0.9%) of patients. In the propensity matched cohort, exposure was associated with lower mortality (relative risk RR, 0.73; 95% CI, 0.65-0.83; P < .001; number need to treat NNT, 241; 95% CI, 173-397). When stratified by cumulative numbers of Revised Cardiac Risk Index factors, β-blocker exposure was associated with significantly lower mortality among patients with 2 factors (RR, 0.63 95% CI, 0.50-0.80; P < .001; NNT, 105 95% CI, 69-212), 3 factors (RR, 0.54 95% CI, 0.39-0.73; P < .001; NNT, 41 95% CI, 28-80), or 4 factors or more (RR, 0.40 95% CI, 0.25-0.73; P < .001; NNT, 18 95% CI, 12-34). This association was limited to patients undergoing nonvascular surgery. β-Blocker exposure was also associated with a lower rate of nonfatal Q-wave infarction or cardiac arrest (RR, 0.67 95% CI, 0.57-0.79; P < .001; NNT, 339 95% CI, 240-582), again limited to patients undergoing nonvascular surgery. Among propensity-matched patients undergoing noncardiac, nonvascular surgery, perioperative β-blocker exposure was associated with lower rates of 30-day all-cause mortality in patients with 2 or more Revised Cardiac Risk Index factors. Our findings support use of a cumulative number of Revised Cardiac Risk Index predictors in decision making regarding institution and continuation of perioperative β-blockade. A multicenter randomized trial involving patients at a low to intermediate risk by these factors would be of interest to validate these observational findings.