This retrospective, cross-sectional study of U.S. hospitals in Medicare's Inpatient Quality Reporting Program aimed to determine whether variation in Sepsis/Septic Shock (Bundle SEP-1) compliance is linked to hospital size and measures of safety and operational efficiency. Two thousand six hundred and fifty-three acute care hospitals in Medicare's Hospital Compare online database were included in the study. Relationships between SEP-1 bundle compliance, hospital size, and indices of operational excellence (including Patient Safety Index [PSI-90], average length of stay [ALOS] and readmission rate) were analyzed. SEP-1 compliance score was inversely associated with staffed bed number (r = −.14, p < .001), PSI-90 (r = −.01, p < .001), and ALOS (r = −.13, p < .001) in a multivariate analysis. Hospitals in the lowest versus highest quartile by bed number had SEP-1 compliance score of 49.8 ± 20.2% versus 46.9 ± 16.8%, p < .001. Hospitals in the lowest versus highest quartile for SEP-1 score had an ALOS of 5.0 ± 1.2 days versus 4.7 ± 1.1 days and PSI-90 rate of 1.03 ± 0.22 versus 0.98 ± 0.16, p < .001 for both. Although this does not establish a causal relationship, it supports the hypothesis that the ability of hospitals to successfully implement SEP-1 is associated with superior performance in key measures of operational excellence.