Hemodialyzer reuse is commonly practiced in the United States. Recent studies have raised concerns about the mortality risk associated with certain reuse practices. We evaluated adjusted mortality risk during 1- to 2-year follow-up in a representative sample of 12,791 chronic hemodialysis patients treated in 1,394 dialysis facilities from 1994 through 1995. Medical record abstraction provided data on reuse practice, use of bleach, dialyzer membrane, dialysis dose, and patient characteristics and comorbidity. Mortality risk was analyzed by bootstrapped Cox models by (1) no reuse versus reuse, (2) reuse agent, and (3) dialyzer membrane with and without the use of bleach, while considering dialysis and patient factors. The relative risk (RR) for mortality did not differ for patients in reuse versus no-reuse units (RR = 0.96; 95% confidence interval [CI], 0.86 to 1.08; P > 0.50), and similar results were found with different levels of adjustment and subgroups (RR = 1.01 to 1.05; 95% CI, lower bound > 0.90, upper bound < 1.19 each; each P > 0.40). The RR for peracetic acid mixture versus formalin varied significantly by membrane type and use of bleach during reprocessing, achieving borderline significance for synthetic membranes. Among synthetic membranes, mortality was greater with low-flux than high-flux membranes (RR = 1.24; 95% CI, 1.02 to 1.52; P = 0.04) and without than with bleach during reprocessing (RR = 1.24; 95% CI, 1.01 to 1.48; P = 0.04). Among all membranes, mortality was lowest for patients treated with high-flux synthetic membranes (RR = 0.82; 95% CI, 0.72 to 0.93; P = 0.002). Although mortality was not greater in reuse than no-reuse units overall, differences may exist in mortality risk by reuse agent. Use of high-flux synthetic membrane dialyzers was associated with lower mortality risk, particularly when exposed to bleach. Clearance of larger molecules may have a role.