Background: Depression increases the risk of mortality in hemodialysis patients. Alexithymia, a disorder of affect regulation, has also been reported to be associated with mortality risk in the general population. We conducted a prospective study to estimate the independent impact of depression and alexithymia on long-term mortality. Methods: A total of 230 hemodialysis outpatients, with a mean age of 56.3 ± 9.6 years, completed a batch of self-report measures including the Beck Depression Inventory-II (BDI-II), the 20-item Toronto Alexithymia Scale (TAS-20) and the 36-item Short Form Health Survey (SF-36). Survival status was confirmed every 6 months for up to 5 years. The presence of depression and alexithymia was defined by a BDI-II score of ≧14 and a TAS-20 score of ≧61, respectively. Results: During the follow-up period, 27 deaths were confirmed. Both depression and alexithymia were associated with an increased risk for all-cause mortality; the age- and sex-adjusted hazard ratio for depression was 2.36 (95% CI: 1.08–5.15; p = 0.03) and that for alexithymia was 4.29 (95% CI: 1.95–9.42; p < 0.001). Depression lost its statistical significance after controlling for alexithymia, whereas alexithymia remained significant even after adjusting for the baseline depression, health status (the summary scores of the SF-36), marital status and clinical covariates (multivariate adjusted hazard ratio = 3.62; 95% CI: 1.32–9.93; p = 0.01). Conclusions: Alexithymia is a strong independent risk factor for all-cause mortality in hemodialysis patients.