Objective. To estimate the proportion of healthcare-associated infections (HAIs) in US hospitals that are “reasonably preventable,” along with their related mortality and costs. Methods. To estimate preventability of catheter-associated bloodstream infections (CABSIs), catheter-associated urinary tract infections (CAUTIs), surgical site infections (SSIs), and ventilator-associated pneumonia (VAP), we used a federally sponsored systematic review of interventions to reduce HAIs. Ranges of preventability included the lowest and highest risk reductions reported by US studies of “moderate” to “good” quality published in the last 10 years. We used the most recently published national data to determine the annual incidence of HAIs and associated mortality. To estimate incremental cost of HAIs, we performed a systematic review, which included costs from studies in general US patient populations. To calculate ranges for the annual number of preventable infections and deaths and annual costs, we multiplied our infection, mortality, and cost figures with our ranges of preventability for each HAI. Results. As many as 65%–70% of cases of CABSI and CAUTI and 55% of cases of VAP and SSI may be preventable with current evidence-based strategies. CAUTI may be the most preventable HAI. CABSI has the highest number of preventable deaths, followed by VAP. CABSI also has the highest cost impact; costs due to preventable cases of VAP, CAUTI, and SSI are likely less. Conclusions. Our findings suggest that 100% prevention of HAIs may not be attainable with current evidence-based prevention strategies; however, comprehensive implementation of such strategies could prevent hundreds of thousands of HAIs and save tens of thousands of lives and billions of dollars.