Background: Each year approximately 1.7 million occur in the United States causing significant morbidity and nearly 100,000 deaths. Clostridium difficile infection (CDI) has become the most common healthcare- associated infection (HAI) in U.S. hospitals causing half a million infections and 30,000 deaths. CDI ranges from asymptomatic colonization, mild to severe diarrhea, pseudomembranous colitis, toxic megacolon, colonic perforation, and death. Risk factors for CDI include older age, comorbidity, hospitalization, exposure to others with CDI, and antibiotic use. The increasing incidence of C. difficile and emergence of new epidemic strain has resulted in outbreaks in healthcare settings. Prevention of healthcare-onset (HO) CDI has quickly become a priority for most hospitals. Hospital prevention measures are limited to modifiable risk factors (i.e., prudent antibiotic use and limiting exposure to C. difficile). Hospital exposure to C. difficile can occur directly (i.e., hands or clothing of healthcare workers) or indirectly (i.e., environmental surfaces or shared equipment) so infection prevention measures focus on healthcare worker hand hygiene, healthcare worker barrier precautions (i.e., use of gowns and gloves) and cleaning and disinfection of the hospital environment and reusable medical equipment. However, these interventions are limited to symptomatic patients who test positive for CDI. Asymptomatic patients serve as a reservoir for cross contamination, but microbiological screening for asymptomatic carriage of C. difficile is not routinely performed in healthcare. Gloving for all patient contacts may interrupt transmission from asymptomatic patients colonized with C. difficile. Objectives: The overall purpose of the proposed study is to determine the effectiveness of healthcare worker use of gloves for all patient contact for reducing acquisition of C. difficile and hospital-onset CDI in inpatient hospital units. The main objective of the study is to compare the effects of universal gloving for all patient contact to the current standard of care (i.e., glove and gown only for known CDI cases). The specific aims are 1) Compare the effects of universal gloving for all patient contact to the current standard of care on C. difficile acquisition rates in hospitalized patients; 2) Compare the effects of universal gloving compared to standard of care gloving on CDI rates, other healthcare-associated infections, 30-day mortality and unit length of stay; 3) Evaluate intervention fidelity, the cost and stakeholder experiences. Methods: The study will be a cluster randomized trial (CRT) in ten inpatient VA hospital units. In the pre- intervention period we will conduct preparatory work including recruiting hospitals, training research assistants, securing IRB approval, identifying current practices, finalizing monitoring and observation plans and measuring baseline C. difficile acquisition rates. This will be followed by an intervention period execu...