Background: Gastro-esophageal reflux disease is a chronic disease that is widespread globally. This disease negatively affects the patient's productivity and quality of life. Therefore, the patient's adherence to treatment based on his health knowledge of the disease and its complications, as well as following a healthy lifestyle positively affects their quality of life. Quite limited studies explored that adherence of esophageal reflux patients and their quality of life separately. Therefore, our study was aimed to determine the relationship between GERD patients' knowledge, medication-adherence, and their quality of life. Research design: We used a quantitative correlational design. Subjects: a convenience sample of 320 GERD patients who were met the inclusion criteria were selected randomly. Setting: The study conducted at medical outpatient clinics at Beni-Suef and Zagazig University Hospitals. Tools: Socio-demographic data-sheet, Knowledge assessment sheet, Mourisky Medication-Adherence Scale, Quality of Life in Reflux, and Dyspepsia Questionnaire, and Visual Numeric Pain Scale were used to collect relevant data. Results: The participants' total knowledge score was poor with a mean score of 68±2.42. A positive correlation with a highly statistically significant difference was shown between the total medication-adherence score and QoL of the participants (p=0.04). Conclusion and recommendation: The participants' overall knowledge about GERD was poor. A positive, statistically significant relationship was detected in-between the participants' total knowledge score, their affected QoL, and their adherence level to medication. Obviously, further research is needed to educate GERD patients about their disease and the importance of adherence to medication. Key words: Adherence, Compliance, Gastro-Esophageal Reflux [GERD], Knowledge, Lifestyle, Quality of Life.