Background: Ventricular assist devices (VADs) are often necessary to maintain circulation in patients with heart failure prior to cardiac transplantation. However, the use of such devices has been reported to be associated with a high incidence of development of human leukocyte antigen (HLA) antibodies, due perhaps, according to some investigators, to immune-activating properties of the VAD itself. We looked at HLA antibody formation in our patients during VAD support to determine the rate and potential causes of antibody formation. Methods: Between 1995 and 2000, 54 patients were placed on a VAD at our institution. We reviewed clinical and blood transfusion history and HLA antibody testing of the 29 patients without HLA antibodies prior to implantation. HLA antibody testing was performed by an anti-globulin-augmented cytotoxicity method or by a commercial enzyme-linked immunoassay (ELISA) kit. Results: Eight of 29 patients (28%) developed HLA antibodies. Patients who developed HLA antibodies after VAD implantation received significantly more total peri- and post-operative transfusions than did those who remained negative (99 transfusions vs 34 transfusions, p = 0.0014). Within this small study group, gender, age, etiology of heart failure, previous cardiac surgery and duration of VAD support showed no statistically significant correlation with formation of HLA antibodies. Conclusions: Our data suggest that HLA alloimmunization during VAD support may be due to extensive blood transfusion. The rate of HLA alloimmunization does not appear to be greater than that reported in other populations of multi-transfused patients. Leukoreduction of cellular components, as well as plasma, or other initiatives is needed to reduce the rate of alloimmunization and, potentially, the wait to transplantation.