Healthcare associated infection is a leading cause of preventable illness and death. Methicillin-resistant Staphylococcus aureus (MRSA) is a virulent, multi-drug resistant infection increasingly seen across healthcare settings. This pragmatic, cluster-randomized trial to determine the most effective approach for reducing the rates of MRSA was implemented in 43 hospitals, including 74 ICUs and 74,256 patients. Compared to baseline, modeled hazard ratios for MRSA clinical isolates were 0.92 for those undergoing screening isolations, 0.75 for targeted decolonization, and 0.63 for universal decolonization. Universal decolonization resulted in significantly greater reduction in blood stream infections than the other two studied approaches for infection reduction.