Background: A successful left ventricular assist device (LVAD) long-term support in an outpatient setting demands that device-related complications are reduced to a minimum. We hypothesized that late onset driveline infections have serious implications on the anticipated application of LVAD as permanent therapy. Methods: Between 1996 and 2005, 73 patients were implanted with the Novacor (World Heart Corp, Ottawa, Ontario, Canada; n = 35) or the HeartMate (Thoratec Corp, Pleasanton, CA; n = 38) as either bridge to transplantation (n = 44) or destination therapy (n = 29). Our analysis focused on patients with late-onset infection (≥30 days) of the driveline exit site with prior clinical healing of all incisions. Results: Late driveline infections developed in 17 patients (23%) at a median of 158 days (intraquartile range [IQR]: 68 to 213 days) after implantation. The median duration of support in this subgroup was 400 days (IQR, 283 to 849 days). Despite an aggressive treatment algorithm, repeat surgical revision was needed in 12 patients, up to six times in 2 individuals. In 6 patients, the infection progressed to pump pocket infections that led to urgent heart transplantation (n = 4) or explantation (n = 2). The individual risk that a driveline infection would develop dramatically increased with the duration of support, reaching 94% at 1 year. Multivariate analysis identified duration of support (p < 0.001) and documented trauma at the driveline exit site (p < 0.001) as independent predictors of infection. Number and duration of readmissions to the hospital significantly increased (p < 0.001), and long-term follow-up for survival (4.4 ± 2.2 years, 100% complete) showed a trend towards impaired outcome after driveline infection (5-year survival: 41% versus 70%, p = 0.10). Conclusions: Long-term LVAD support in the current series was jeopardized by late-onset driveline infections, which occurred in all patients with support duration longer than 1 year. Once driveline infections developed, they were difficult to control and significantly increased morbidity.