Cytomegalovirus (CMV)-seropositive patients with ESRD may have more CD4+T cells lacking the co-stimulatory molecule CD28 (CD4+CD28null) than CMV-seronegative patients. Increased numbers of CD28null T cells associates with epoetin nonresponsiveness in patients with ESRD, but whether expansion of CD4+CD28null T cells in CMV-seropositive patients associates with demand for epoetin is unknown. In a cohort of 129 stable patients with ESRD, CMV seropositivity significantly associated with a lower hemoglobin level in predialysis patients (12.5 versus 11.5 g/dl; P < 0.02). CMV seropositivity did not associate with average hemoglobin level in hemodialysis patients, but CMV-seropositive patients required significantly more epoetin (median 12,000 versus 6300 U/wk; P = 0.02). Multivariate linear regression analysis identified CMV seropositivity as the only variable significantly associated with hemoglobin levels in predialysis patients and epoetin dosages in hemodialysis patients. In CMV-seropositive hemodialysis patients, the number of circulating CD4+CD28null T cells positively correlated with epoetin dosage. These CD4+CD28null T cells were proinflammatory; they were capable of producing large amounts of IFN-γ and TNF-α. In conclusion, expansion of CD4+CD28null T cells in CMV-seropositive patients with ESRD associates with increased demand for epoetin. Copyright