<b><i>Background:</i></b> There are limited data regarding the relationship between depression and mortality in hemodialysis (HD) patients. <b><i>Methods:</i></b> Among 323 patients receiving maintenance HD, depression symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale, with a score of ≥16 consistent with depression. Adjusted Cox proportional-hazards models with additional analyses incorporating antidepressant medication use were used to evaluate the association between depression and mortality. Baseline CES-D scores were used for the primary analyses, while secondary time-dependent analyses incorporated subsequent CES-D results. <b><i>Results:</i></b> The mean age was 62.9 ± 16.5 years, 46% of the subjects were women and 22% were African-American. The mean baseline CES-D score was 10.7± 8.3, and 83 (26%) participants had CES-D scores ≥16. During a median (25th, 75th) follow-up of 25 (13, 43) months, 154 participants died. After adjusting for age, sex, race, primary cause of kidney failure, dialysis vintage and access, baseline depression was associated with an increased risk of all-cause mortality (HR 1.51 and 95% CI 1.06-2.17). This attenuated with further adjustment for cardiovascular disease, smoking, Kt/V, serum albumin, log C-reactive protein and use of antidepressants (HR 1.21 and 95% CI 0.82-1.80). When evaluating time-dependent CES-D, depression remained associated with increased mortality risk in the fully adjusted model (HR 1.44 and 95% CI 1.00-2.06). <b><i>Conclusions:</i></b> Greater symptoms of depression are associated with an increased risk of mortality in HD patients, particularly when accounting for the most proximate assessment. This relationship was attenuated with adjustment for comorbid conditions, suggesting a complex relationship between clinical characteristics and depression symptoms. Future studies should evaluate whether treatment for depression impacts mortality among HD patients.