Higher levels of depressive affect in ESRD patients treated with HD are associated with increased mortality. The effects of depression on patient survival are of the same order of magnitude as medical risk factors. Our findings using both controls for factors possibly confounded with depressive affect in patients with ESRD and time-varying covariate analyses may explain the inconsistent results of previous studies of depression and mortality in ESRD patients. Time-varying analyses in longitudinal studies may add power to defining and sensitivity to establishing the association of psychosocial factors and survival in ESRD patients. The mechanism underlying the relationship of depression and survival and the effect of interventions to improve depression in HD outpatients and general medical inpatients should be studied.