Hepatitis C virus (HCV) infection is common among patients with end-stage renal disease (ESRD). However, the effect of HCV infection on survival among ESRD patients, and the impact of renal transplantation on the course of HCV infection has not been adequately defined. Sera from patients on the renal transplant waiting list at the New England Organ Bank between November 1986 and June 1990 were tested for anti-HCV using a third generation ELISA. All anti-HCV positive patients and a 1:1 ratio of randomly selected anti-HCV negative patients comprised the study sample. Duration of follow-up was calculated from the date of the first available serum specimen until death, loss to follow-up or December 31, 1995, whichever occurred earlier. Multivariate analysis of risk factors for mortality was performed using a Cox proportional hazards model which included anti-HCV as a time-independent (baseline) variable, transplantation as a time-dependent (follow-up) variable, and independently significant baseline covariates. Anti-HCV was detected in 287 (19%) of 1544 patients in whom sera were available, and 286 anti-HCV negative patients served as controls. Complete information was available in 496 (87%) of these 573 patients. Median follow-up was 73 months (range 1 to 110 months), during which time 302 (61%) patients underwent renal transplantation and 154 (31%) patients died. For anti-HCV positive patients compared to anti-HCV negative patients, the relative risk of death (and 95% confidence intervals) from all causes was 1.41 (1.01 to 1.97) and due to liver disease or infection was 2.39 (1.28 to 4.48). For patients who underwent transplantation compared to those who remained on dialysis, the relative risk of death from all causes between 0 to 3 months, 3 to 6 months, seven months to four years, and after four years was 4.75 (2.76 to 8.17), 1.76 (0.75 to 4.13), 0.31 (0.18 to 0.54) and 0.84 (0.51 to 1.37), respectively. There was no interaction between the effect of anti-HCV status as baseline and subsequent transplantation (P = 0.93), meaning that the association between treatment modality and survival was similar among anti-HCV positive and negative patients, at all intervals after transplantation. We conclude that HCV infection at the time of referral for transplantation is associated with an increased risk of death, irrespective of whether patients remain on dialysis or undergo transplantation. Transplantation has a beneficial rather than adverse effect on long-term survival in anti-HCV positive patients. Hence, anti-HCV positive status alone is not a contraindication for renal transplantation.