Background: The aim of the present study was to determine the relationship between the quality of life of patients on renal replacement therapy and the Symptomatology they presented. Methods: Cross-sectional descriptive observational study: quality of life was assessed by means of the KDQOL-SF questionnaire, Symptomatology by the Palliative Care Outcome Scale-Symptoms Renal questionnaire, and sociodemographic and clinical data of patients in the Hemodialysis Unit (HD) of the Hospital General Universitario de Ciudad Real (HGUCR) by means of personal interviews and clinical history data. Results: A total of 105 patients participated in the study, 63 (60.57%) men and 42 (40.38%) female. The mean age was 62.5 dt (14.84) years. Of these, 43 (41%) were on peritoneal dialysis and 62 (59%) were on hemodialysis. The mean quality of life score was 44.89 dt (9.73). People on hemodialysis treatment presented a better quality of life than those on PD treatment: 49.66 dt (9.73) vs. 38.13 dt (9.12) t = 7.302, p < 0.001. A higher score on the symptom impairment scale (post-renal) correlated with worse scores on the total quality of life score: r = −0.807, p < 0.001. It was observed that those who improved the distress symptom scored better on the total quality of life questionnaire: 50.22 dt (8.44) vs. 46.42 dt (9.05), p < 0.001. Conclusions: The presence and management of the large number of symptoms that appear as side effects, such as distress or depression, could determine changes in some components of quality of life.