Heparin-induced thrombocytopenia is a serious complication of heparin therapy that can lead to thromboembolism, cardiovascular events, and death. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing antibodies to the platelet factor 4-heparin (PF4-H) complex. We sought to determine the association between PF4-H antibodies and mortality in a prospective cohort of 419 asymptomatic hemodialysis patients. Pre-dialysis blood samples were screened for nonspecific PF4-H antibodies, and all positive and indeterminate samples were subsequently tested using immunoglobulin (Ig)G-specific PF4-H and platelet serotonin-release assays. During a median follow-up of 2.5 years there were 129 all-cause deaths. After controlling for potential confounding variables, the relative risk of death was significantly increased for patients with IgG-specific PF4-H antibodies and further elevated with an indeterminate serotonin-release assay. Our study suggests that IgG-specific PF4-H antibody formation is associated with increased mortality in hemodialysis patients.