The increasing use of implanted biomaterial devices has made it evident that no material is biologically inert. As a result of direct contact with elements of the blood circulation, such as during hemodialysis or after left ventricular assist device (LVAD) implantation, significant changes in systemic immunologic and thrombostatic functions occur. The clinical success of LVAD implantation has, nevertheless, been accompanied by complications arising from an aberrant state of monocyte and T-cell activation, leading to heightened susceptibility of circulating CD4 T cells to undergo activation-induced cell death; this results in progressive defects in cellular immunity and an increased risk of serious infection. Because of the increased state of T-cell activation and the selective loss of Th1 cytokine producing CD4 T cells, LVAD recipients also develop B-cell hyperreactivity and dysregulated immunoglobulin syntheses by unopposed production of Th2 cytokines and increased CD40 Ligand-CD40 interactions. LVADs are currently being evaluated as a permanent therapy for end-stage heart failure. Because these immune dysfunctions appear to be related to the effects of excessive biomaterial associated T-cell activation, future efforts will need to be directed at either altering the physical properties of the materials interacting with the host circulation or pharmacological intervention aimed at inhibiting T-cell activation.