Patients with end-stage renal disease have significant impairments in health related quality of life (HRQOL). The determinants of HRQOL, including the effect of dialysis adequacy, have not been well studied. This study was designed to investigate whether dialysis adequacy is associated with HRQOL in hemodialysis patients. A cross-sectional survey of 128 patients who had been on hemodialysis for more than 6 months was conducted. Baseline information on demographic factors and detailed clinical information was collected. Average Kt/V levels (for the 3 months preceding HRQOL assessment) were determined. HRQOL was assessed with the Kidney Disease Quality of Life Short Form, the Short Form-36 (SF-36), and the EuroQol EQ-5D. Multiple linear regression was performed to control for differences in important baseline covariates. Patients with average Kt/V levels greater than or equal to 1.3 had better HRQOL as measured by significantly higher scores (p < 0.05) in 4 of 11 kidney disease targeted domains, 6 of 8 SF-36 domains, and on the EQ-5D visual analog scale and index score. Using multiple linear regression to control for important covariates, the adjusted EQ-5D index score was higher by 0.036 (95% confidence intervals 0.015, 0.057) for each 0.1 increment in Kt/V, which is both statistically and clinically significant. Dialysis adequacy was significantly associated with HRQOL in hemodialysis patients. Controlled studies that examine the effect of increasing Kt/V on HRQOL are needed.