Previously reported associations between hospital-level antibiotic use and hospital-onset Clostridioides difficile infection (HO-CDI) were reexamined using 2012-2018 data from a new cohort of US acute-care hospitals. This analysis revealed significant positive associations between total, third-generation, and fourth-generation cephalosporin, fluoroquinolone, carbapenem, and piperacillin-tazobactam use and HO-CDI rates, confirming previous findings.