This article describes the infectious complications that occurred among four of the longest-term recipients of the Jarvik-7 artificial heart. Infection arising from the drive lines, with spread to the mediastinal periprosthetic space, was the major limiting factor in long-term use of the device in these patients. Periprosthetic infections were due to coagulase-negative staphylococci, Staphylococcus aureus, Pseudomonas aeruginosa, and other Pseudomonas species. Other infectious complications incurred by some of the patients included pneumonia, empyema, urinary tract infection, and intravascular line sepsis with Candida. Intensive antimicrobial therapy for prolonged periods seemed to suppress but not to eradicate infection and was accompanied by the appearance of multiresistant bacterial strains. Complications of antimicrobial therapy included diarrhea secondary to overgrowth with Clostridium difficile in two patients. Use of the current device for more than 30 days should be considered extraordinary and should be reserved for patients for whom no other form of life support is available.