We compared, in three intensive care units, colonization of hubs with hub protection boxes or hubs with needleless closed connectors; 137 central venous catheters and 451 hubs were randomized in two groups with similar characteristics. Catheter and hub colonization were not different between the two groups. Among 30 colonized catheters, the same isolate was found in only two hubs; hub contamination rarely is responsible for catheter colonization in short-term catheters. Further studies are required to evaluate the benefit of protected hubs compared with unprotected hubs.