Background: To provide a standardized, risk-adjusted method for summarizing antimicrobial use (AU), the Centers for Disease Control and Prevention developed the standardized antimicrobial administration ratio, an observed-to-predicted use ratio in which predicted use is estimated from a statistical model accounting for patient locations and hospital characteristics. The infection burden, which could drive AU, was not available for assessment. To inform AU risk adjustment, we evaluated the relationship between the burden of drug-resistant gram-positive infections and the use of anti-MRSA agents. Methods: We analyzed data from acute-care hospitals that reported ≥10 months of hospital-wide AU and microbiologic data to the National Healthcare Safety Network (NHSN) from January 2018 through June 2019. Hospital infection burden was estimated using the prevalence of deduplicated positive cultures per 1,000 admissions. Eligible cultures included blood and lower respiratory specimens that yielded oxacillin/cefoxitin–resistant Staphylococcus aureus (SA) and ampicillin-nonsusceptible enterococci, and cerebrospinal fluid that yielded SA. The anti-MRSA use rate is the total antimicrobial days of ceftaroline, dalbavancin, daptomycin, linezolid, oritavancin, quinupristin/dalfopristin, tedizolid, telavancin, and intravenous vancomycin per 1,000 days patients were present. AU rates were modeled using negative binomial regression assessing its association with infection burden and hospital characteristics. Results: Among 182 hospitals, the median (interquartile range, IQR) of anti-MRSA use rate was 86.3 (59.9–105.0), and the median (IQR) prevalence of drug-resistant gram-positive infections was 3.4 (2.1–4.8). Higher prevalence of drug-resistant gram-positive infections was associated with higher use of anti-MRSA agents after adjusting for facility type and percentage of beds in intensive care units (Table 1). Number of hospital beds, average length of stay, and medical school affiliation were nonsignificant. Conclusions: Prevalence of drug-resistant gram-positive infections was independently associated with the use of anti-MRSA agents. Infection burden should be used for risk adjustment in predicting the use of anti-MRSA agents. To make this possible, we recommend that hospitals reporting to NHSN’s AU Option also report microbiologic culture results.