Abstract. Kidneys from donors who are positive for hepatitis C virus (DHCVϩ) have recently been identified as an independent risk factor for mortality after renal transplantation. However, it has not been determined whether risk persists after adjustment for baseline cardiac comorbidity or applies in the era of modern immunosuppression. Therefore, a historical cohort study was conducted of US adult cadaveric renal transplant recipients from January 1, 1996, to May 31, 2001 followed until October 31, 2001. A total of 36,956 patients had valid donor and recipient HCV serology. Cox regression analysis was used to model adjusted hazard ratios for mortality and graft loss, respectively, adjusted for other factors, including comorbid conditions from Center for Medicare and Medicaid Studies Form 2728 and previous dialysis access-related complications. It was found that DHCVϩ was independently associated with an increased risk of mortality (adjusted hazard ratio, 2.12, 95% confidence interval, 1.72 to 2.87; P Ͻ 0.001), primarily as a result of infection. Mycophenolate mofetil was associated with improved survival in DHCVϩ patients, primarily related to fewer infectious deaths. Adjusted analyses limited to recipients who were HCVϩ, HCV negative, or age 65 and over, or by use of mycophenolate mofetil confirmed that DHCVϩ was independently associated with mortality in each subgroup. It is concluded that DHCVϩ is independently associated with an increased risk of mortality after renal transplantation adjusted for baseline comorbid conditions in all subgroups. Recipients of DHCVϩ organs should be considered at high risk for excessive immunosuppression.The expected clinical course of hepatitis C infection as it affects organ transplant recipients, as well as the use and effect of kidneys from donors who are positive for hepatitis C, remain controversial topics in renal transplantation. Recently published data confirmed that kidneys from donors who were hepatitis C positive (HCVϩ) were associated with an independently increased risk of death in renal transplant recipients regardless of recipient HCV status (1). However, donor hepatitis C seropositivity (DHCVϩ) was not independently associated with mortality when limited to patients with valid information (Centers for Medicare and Medicaid Studies [CMS] Form 2728) on comorbid conditions at the time of dialysis initiation. This may have been because of the relatively small numbers of transplant recipients for whom complete data were available during the study period or because cardiovascular comorbidity was actually lower in patients who received DHCVϩ kidneys, yet the mortality risk for recipients of DHCVϩ kidneys was still greater than for patients who received DHCVϪ kidneys. Possibly, recipients of DHCVϩ kidneys were sicker to start with and thus had a higher risk of death unrelated to receiving a DHCVϩ kidney. Since that study, there have been substantial changes in maintenance immunosuppression practices in the United States. In particular, recent reports have confirmed tha...