In cancer patients with long-term central venous catheters (CVC), removal and reinsertion of a new CVC at a different site might be difficult because of the unavailability of accessible vascular sites. In vitro and animal studies showed that a minocycline-EDTA-ethanol (M-EDTA-EtOH) lock solution may eradicate microbial organisms in biofilms, hence enabling the treatment of central line-associated bloodstream infections (CLABSI) while retaining the catheter in situ. Between April 2013 and July 2014, we enrolled 30 patients with CLABSI in a prospective study and compared them to a historical group of 60 patients with CLABSI who had their CVC removed and a new CVC inserted. Each catheter lumen was locked with an M-EDTA-EtOH solution for 2 h administered once daily, for a total of 7 doses. Patients who received locks had clinical characteristics that were comparable to those of the control group. The times to fever resolution and microbiological eradication were similar in the two groups. Patients with the lock intervention received a shorter duration of systemic antibiotic therapy than that of the control patients (median, 11 days versus 16 days, respectively; P < 0.0001), and they were able to retain their CVCs for a median of 74 days after the onset of bacteremia. The M-EDTA-EtOH lock was associated with a significantly decreased rate of mechanical and infectious complications compared to that of the CVC removal/reinsertion group, who received a longer duration of systemic antimicrobial therapy. (This study has been registered at ClinicalTrials.gov under registration no. NCT01539343.) L ong-term central venous catheters have become a lifeline for patients with cancer, those undergoing transplant, or longterm hemodialysis patients. More than five million central venous catheters (CVCs) are inserted annually in the United States, resulting in approximately 400,000 episodes of central line-associated bloodstream infections (CLABSI) and catheter-related bloodstream infections (CRBSI) (1, 2), each associated with an attributable mortality of 12 to 35% (3, 4) and an attributable cost of $34,508 to $56,000 per episode (5). For CLABSI/CRBSI associated with long-term CVCs (including cuffed/tunneled CVCs or ports with a dwell time of Ͼ30 days), the lumen of the catheter is the major source of colonization and subsequent bacteremia (6).The conventional standard of care in the management of CLABSI/CRBSI involves removal of the infected CVC and replacement with a new catheter at a different vascular site (7). However, in cancer, transplant, and hemodialysis patients with long-term catheters, removal of the CVC and reinsertion of a new catheter at a different site might be difficult or even impossible because of the unavailability of accessible vascular sites. Furthermore, these seriously ill patients with CLABSI/CRBSI and sepsis often have underlying thrombocytopenia or coagulopathy, which would make reinsertion of a new CVC at a different site risky given these comorbidities and related mechanical complications, such as blee...