This study explores the infrastructural and organizational risk factors for healthcare-associated (HCA) Clostridioides difficile infections (CDIs) and methicillin-resistant Staphylococcus aureus (MRSA) in hospitals. This is a retrospective observational study involving all eligible inpatient units from 12 hospitals in British Columbia, Canada, from April 1, 2020 to September 16, 2021. The outcomes were the average HCA CDI or MRSA rates. Covariates included, but were not limited to, infection control factors (eg, hand hygiene rate), infrastructural factors (eg, unit age), and organizational factors (eg, hallway bed utilization). Multivariable regression was performed to identify statistically significant risk factors. Older units were associated with higher HCA CDI rates (adjusted relative risk [aRR]: 0.012; 95%confidence interval (CI) [0.004, 0.020]). Higher HCA MRSA rates were associated with decreased hand hygiene rate (aRR: -0.035; 95%CI [-0.063, -0.008]), higher MRSA bioburden (aRR: 9.008; 95%CI [5.586, 12.429]), increased utilization of hallway beds (aRR: 0.680; 95%CI [0.094, 1.267]), increased nursing overtime rate (aRR: 5.018; 95%CI [1.210, 8.826]), and not keeping the clean supply room door closed (aRR: -0.283; 95%CI [-0.536, -0.03]). The study confirmed the multifaceted nature of infection prevention and emphasized the importance of interdepartmental collaboration to improve patient safety.