This retrospective cohort study evaluates the effect of chronic antimicrobial suppression (CAS) therapy on clinical outcomes in patients with continuous-flow left ventricular assist devices (CF-LVADs) and a history of device-related infection. Patients with CF-LVAD implantation between January 2008 and August 2011 who received systemic CAS after index antibiotic treatment of a device-related infection were included. Chronic suppression was defined as continuation of antibiotics for longer than 6 weeks after the index infection. Standard International Society for Heart and Lung Transplantation definitions were used. The primary outcome is failure of CAS, defined as a clinical deterioration resulting in the need for transition from oral to intravenous (IV) therapy or a need to change to a different IV antibiotic, elevation to status 1A on the transplant list as a result of ongoing infection, or device/driveline exchange. Of 140 patients screened, 16 patients were included (69% male, 63% African American, median age 52 years). The driveline was the most common site of infection (69%). Organisms isolated included Gram-positive cocci (n = 7), Gram-negative bacilli (n = 10), and Candida (n = 1). Oral trimethoprim/sulfamethoxazole treatment was most commonly used for suppression (37.5%). Failure of CAS occurred in 5/16 (31%) patients after a mean time of 175 days on therapy (range 10-598). The majority of failures (60%) required device exchanges. Side effects of nausea, vomiting, or diarrhea were reported in three patients; all required changes in oral suppression regimen. Clostridium difficile infection was noted in two patients. These results, which must be confirmed by a larger analysis, suggest that one-third of CF-LVAD patients may develop recurrent infections while on CAS therapy.