The Centers for Medicare and Medicaid Services (CMS) Hospital Compare central line-associated bloodstream infection (CLABSI) data and private databases containing new-generation intravenous needleless connector (study NC) use at the hospital level were linked. The relative risk (RR) of CLABSI associated with the study NCs was estimated, adjusting for hospital characteristics. Among 3074 eligible hospitals in the 2013 CMS database, 758 (25%) hospitals used the study NCs. The study NC hospitals had a lower unadjusted CLABSI rate (1.03 vs 1.13 CLABSIs per 1000 central line days, P < .0001) compared with comparator hospitals. The adjusted RR for CLABSI was 0.94 (95% confidence interval: 0.86, 1.02; P = .11).