Reducing central line-associated bloodstream infections (CLABSI) to zero is especially challenging in long-term acute care (LTAC) hospitals because patients usually have the line in place at admission. The central venous line may have been in place from days to weeks before admission. The LTAC thus has no control over the site selection, catheter selection, insertion protocol, and care and maintenance the catheter received before admission. Using comprehensive practice-based evidence for clinical practice improvement, our LTAC used different needleless connectors during a 3-year period to achieve zero CLABSIs. The sample data offers a rare opportunity to compare different needleless connectors and in a wide sample of complex patient diagnoses. Needleless connector design in combination with nursing care and management can achieve zero CLABSI,s even in the challenging LTAC environment.