The objective of this study was to evaluate whether the apparent relationship demonstrated in prior studies between iron dosing and mortality in hemodialysis (HD) patients was confounded by incomplete representation of iron dosing and morbidity over time. A cohort study was conducted among 32,566 patients who received at least 1 yr of HD at the Fresenius Medical Corporation dialysis centers during 1996 to 1997. The outcome measure was all-cause mortality through mid-1998. A total of 19 demographic, comorbidity, and laboratory characteristics were available. By proportional hazards analysis, no adverse effect on 2-year survival was found for baseline iron dose over 6 mo of < or = 1000 mg, but statistically significant elevated mortality was demonstrated for iron doses >1000 mg to 1800 mg (adjusted hazards ratio [HR] = 1.09; 95% confidence interval [CI], 1.01 to 1.17) and >1800 mg (adjusted HR = 1.18; 95% CI, 1.09 to 1.27). However, fitting multivariable models that appropriately account for time-varying measures of iron administration as well as other fixed and time-varying measures of morbidity, the authors found no statistically significant association between any level of iron administration and mortality. This study suggests that previously observed associations between iron administration and higher mortality may have been confounded, and it provides cautious support for the safety of the judicious administration of cumulative iron doses >1000 mg over 6 mo if needed to maintain target hemoglobin levels among patients treated with maintenance HD.