Health care–associated infections (HAIs) are a serious and common cause of patient harm. The Centers for Disease Control and Prevention (CDC) created the National Healthcare Safety Network to provide information on incidence rates of infections, but most hospitals limit reporting to only certain complications. This multistate prevalence study found that approximately 4% of sampled patients had HAIs. Using a model to extrapolate these findings, nearly 650,000 patients in United States hospitals are estimated to have had an HAI in 2011. Infections associated with devices—including central lines, urinary catheters, and ventilators—have been a major focus of strategies to decrease HAIs, but together they accounted for only about a quarter of all HAIs. Clostridium difficile was responsible for more than 12% of infections, highlighting the importance of efforts to mitigate this life-threatening disease. A recent CDC report suggested the potential promise of antibiotic stewardship programs to decrease C. difficile rates.