While preventing health care–associated infections (HAIs) can save lives and reduce health care costs, efforts designed to eliminate HAIs have had mixed results. Variability in contextual factors such as work culture and management practices has been suggested as a potential explanation for inconsistent results across organizations and interventions. We examine goal-setting as a factor contributing to program outcomes in eight hospitals focused on preventing central line–associated bloodstream infections (CLABSIs). We conducted qualitative case studies to compare higher- and lower-performing hospitals, and explored differences in contextual factors that might contribute to performance variation. We present a goal commitment framework that characterizes factors associated with successful CLABSI program outcomes. Across 194 key informant interviews, internal and external moderators and characteristics of the goal itself differentiated actors’ goal commitment at higher- versus lower-performing hospitals. Our findings have implications for organizations struggling to prevent HAIs, as well as informing the broader goal commitment literature.