The in vitro and in vivo activities of catheters coated with minocycline and rifampin and with chlorhexidine gluconate and silver sulfadiazine were evaluated. When incubated in serum at 37 degrees C, the half-life of the inhibitory activity of catheters coated with minocycline and rifampin was 25 days compared with 3 days for catheters coated with chlorhexidine gluconate and silver sulfadiazine. In a rabbit model, catheters coated with minocycline and rifampin were significantly more efficacious than catheters coated with chlorhexidine and silver sulfadiazine in preventing colonization and infection with Staphylococcus aureus (P < .05). Catheters coated with minocycline and rifampin demonstrated broad-spectrum in vitro inhibitory activity against gram-positive bacteria, gram-negative bacteria, and Candida albicans that was significantly superior to the inhibitory activity of catheters coated with chlorhexidine gluconate and silver sulfadiazine (P < .01). Minocycline and rifampin were also highly efficacious in preventing colonization and infection in vivo.