We implemented universal inpatient Clostridioides difficile screening at an 800-bed hospital. Over 3 years, 2,010 of 47,048 screening tests (4.2%) were positive, with significantly higher rates of C. difficile colonization on transplant units than medical-surgical units: 5.4% (152 of 2,801) versus 4.3% (880 of 20,564), respectively (P = .005). Compliance with screening ranged from 79% to 96%.