Objective. The objective of this study was to examine the association between depression and health-related quality of life (HRQoL) in hemodialysis patients independent of known predictors of HRQoL. Methods and Materials. A descriptive design was used to conduct the study, which involved 140 hemodialysis patients. Depression was measured using the Beck's Depression Inventory (BDI), and HRQoL was measured using the Medical Outcomes Study 36-item Short Form (SF-36). Results. Sixty-two percent of the subjects had a BDI score ≥15. The SF-36 Mental Component Summary (MCS) and Physical Component Summary (PCS) correlated inversely with the BDI score (MCS, r = -0.26, p < 0.01; PCS, r = -0.43, p < 0.01). The PCS score also correlated with age (r = -0.22, p = 0.02) and with hemoglobin (r = 0.21, p = 0.048), and the mean PCS was lower in subjects who had a BDI score ≥15 (22.6 vs. 31.4, p = 0.02). Subjects with a BDI score ≥15 had a lower HRQoL score in all SF-36 domains. The global BDI score was a significant independent predictor of the MCS and PCS after controlling for age, sex, hemoglobin, and serum albumin in multivariate analysis. Conclusions. Depression is common in hemodialysis patients and is associated with a lower HRQoL. We hypothesize that endstage renal disease directly influences depression, which in turn impacts on HRQoL.