Background/Aims: Hemodialysis (HD) represents one of the most commonly used modalities as a renal replacement therapy. Health-related quality of life (HRQoL) is much lower in HD patients than general population. Musculoskeletal (MSK) symptoms are one of the most important health problems that affect patients on maintenance HD. The main purpose of this study was to investigate the association between MSK symptoms and HRQoL among HD patients. Methods: The study was carried out on 200 patients with chronic renal failure on chronic HD at different nephrology units in Egypt. They completed the Arabic version of the Kidney Disease and Quality of Life-Short Form 1.3 Questionnaire and answered the questions of MSK discomfort form based on the Nordic MSK Questionnaire. Results: The mean age of the patients was 50.6 years, 61% were males. Of the 200 HD patients, 180 patients (90%) had MSK manifestations. The most commonly affected part was knee joint (51.5%). Regarding HRQoL, patients with MSK symptoms had significantly lower scores than did patients without on the physical role ( p = 0.035), pain domain ( p = 0.003), general health ( p = 0.017), quality of social interaction ( p = 0.046), and sleep domain ( p = 0.022). Conclusion: MSK manifestations have a negative impact on HRQoL in HD patients. So, early identification and treatment are highly recommended.