Background. Contact precautions (CP) are a widely adopted strategy to prevent cross-transmission of organisms, commonly methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Some hospitals have discontinued CP for patients with MRSA or VRE; however, the impact on hospital-acquired infection rates (HAI) has not been assessed systematically. Methods. Retrospective multicenter interrupted time series between 2002 and 2017 at three academic hospitals. Participating hospitals discontinued CP for patients with contained body fluids who were colonized or infected with MRSA or VRE. The primary intervention was stopping the use of CP. Secondary interventions were horizontal infection prevention strategies. The primary outcomes were rates of central line-associated bloodstream infections, catheter-associated urinary tract infections, mediastinal surgical site infection, and ventilator-associated pneumonia due to MRSA, VRE, or any organism using Centers for Disease Control and Prevention National Healthcare Safety Network surveillance definitions. Results. Central line-associated bloodstream infections, catheter-associated urinary tract infections, mediastinal surgical site infection, and ventilator-associated pneumonia rates trended down at each institution. There were no statistically significant increases in these infections associated with discontinuing CP. Individual horizontal infection prevention strategies variably impacted HAI outcomes. Conclusions. Stopping the routine use of CP for patients with contained body fluids who are colonized or infected with MRSA or VRE did not result in increased HAIs. Bundled horizontal infection prevention strategies resulted in sustained HAI reductions.