Clostridioides difficile is the leading cause of hospital-onset diarrhea and is associated with increased lengths of stay and mortality. While some hospitals have successfully reduced the burden of C. difficile infection (CDI), many still struggle to reduce hospital-onset CDI. Nurses-because of their close proximity to patients-are an important resource in the prevention of hospital-onset CDI. Determine whether there is an association between the nurse work environment and hospital-onset CDI. Survey data of 2016 were available from 15,982 nurses employed in 353 acute care hospitals. These data, aggregated to the hospital level, provided measures of the nurse work environments. They were merged with 2016 hospital-onset CDI data from Hospital Compare, which provided our outcome measure-whether a hospital had a standardized infection ratio (SIR) above or below the national average SIR. Hospitals above the average SIR had more infections than predicted when compared to the national average. In all, 188 hospitals (53%) had SIRs higher than the national average. The odds of hospitals having higher than average SIRs were significantly lower, with odds ratios ranging from 0.35 to 0.45, in hospitals in the highest quartile for all four nurse work environment subscales (managerial support, nurse participation in hospital governance, physician-nurse relations, and adequate staffing) than in hospitals in the lowest quartile. Findings show an association between the work environment of nurses and hospital-onset CDI. A promising strategy to lower hospital-onset CDI and other infections is a serious and sustained commitment by hospital leaders to significantly improve nurse work environments.