Background: Regional changes in United States C. difficile infection (CDI) are not well understood but important for targeting prevention strategies. Methods: Community-onset (CO) CDI was defined as positive C. difficile stool tests collected on or before hospital day 3 (where admission was day 1), reported by acute-care hospitals to the CDC NHSN over 3 years: year 1, July 1, 2015–June 30, 2016; year 2, July 1, 2016–June 30, 2017; year 3, July 1, 2017–June 30, 2018. Healthcare facility-onset CDI (HO-CDI) was similarly defined but with stool collection after hospital day 3. Hospital referral regions (HRRs) were defined by the Dartmouth Atlas of Health Care, and they represent 306 healthcare markets. Standardized infection ratios (SIRs) were calculated using separate multivariable models for (1) CO-CDI events in an emergency department/observation unit (ED/Obs), (2) CO-CDI events among inpatients, and (3) HO-CDI, accounting for facility-level factors, They resulted in ratios of observed to predicted infections, similar to established methods. SIRs were pooled within each facility to create a hospital-identified SIR by summing observed and predicted events for CO-CDI events in both testing locations and HO-CDI events, then pooled by HRR by summing all facility observed and predicted events within the region. Data from facilities not within an HRR were excluded. Results: Total CO-CDI (ED/Obs and inpatient) and HO-CDI events decreased, even as the number of reporting facilities slightly increased over the 3-year period (Fig. 1). Among 306 HRRs in year 3, the median number of hospitals was 10 (IQR, 6–17), with a median of 526 (IQR, 272–1,002) hospital-identified CDI events per HRR. Variables significantly associated with CDI incident rate and included in SIR models 1–3 included C. difficile test type, hospital type, teaching affiliation, hospital bed size, and presence of an ED/Obs unit. Intensive care unit capacity was included in models 2 and 3, and the ratio of hospital admissions to emergency department encounters in model 1. Pooled mean HRR hospital-identified C. difficile SIRs decreased each year (0.972, 0.914, and 0.838), and decreases also varied by HRR (Fig. 2). Conclusions: National decreases in a combined hospital-identified C. difficile SIR are widespread but may be more aggregated in particular regions. Although SIR adjustments were limited to facility-level factors, aggregation of CDI SIR by HRR may be useful for infection preventionists and public health authorities to further understand regional CDI patterns.