Background: Haemodialysis (HD) is a life-saving but burdensome therapy for patients with end-stage renal disease (ESRD) which can bring about significant impairment in health-related quality of life (HRQOL) and outcomes. We therefore sought to determine the patterns of HRQOL and to identify the risk factors for poorer HRQOL in Palestinian patients with HD. Methods: A cross-sectional study was performed during June 2014 to January 2015, using the EuroQOL-5 Dimensions instrument (EQ-5D-5L) for the assessment of HRQOL. ESRD patients undergoing HD at inpatient hospitals from ten different settings at a national level from Palestine were approached for this study. Multiple linear regression was used to estimate which variables were significantly associated with poor HRQOL. The significance level was predetermined at p < level of 0.05 for all tests. Data variables were analysed using SPSS (SPSS Inc., Chicago, IL, USA) programme version 15. Findings: Out of 277 patients, 267 patients consented to participate (response rate of 96 % of all eligible patients approached). Overall, 139 (52.1%) were male, and the mean (standard deviation) age was 53.3 (16.2) years. 177 patients (66.3%) were on HD for less than four years. The reported HRQOL as measured by mean EQ-5D-5L index value and Euro QOL visual analogue (EQ-VAS) score was 0.37 ± 0.44 and 59.38 ± 45.39, respectively. There was a moderate positive correlation between the EQ-VAS and the EQ-5D-5L index value (r = 0.44, p<0.001). There were significant differences between participant groups according to age, body mass index, education level, residency and total number of co-morbid diseases (Kruskal Wallis tests, p-value < 0.05), as well as gender, occupation, and total number of chronic medications (Mann-Whitney test, p-value < 0.05). The results of a multiple linear regression showed a significant association between HRQoL and age, gender, education level, number of chronic medications, and number of co-morbid diseases (p< 0.05). Interpretation: Our results provide insight into a number of associations between patient variables such as demographics, clinical factors, and their HRQOL. Elderly patients, female gender, obese patients, illiterate patients, living in Palestinian refugee camps, and being unemployed were all associated with poor HRQOL. In addition, this study found that HRQOL worsened as the total number of chronic diseases, and the total number of HD medications increased. More directly, the results of this study should help to raise health care providers’ awareness mainly for HD patients with co-morbid diseases and patients with advanced age to improve their quality of life.