Purpose: A multimodal intervention designed and executed to improve therapeutic regimen adherence and quality of life in a sample of Iranian hemodialysis patients. Its feasibility and impact was assessed post intervention. Patients and Methods: This randomized controlled trial (RCT) study was conducted at two hemodialysis wards of the Shahrvand hospital located in Sari, the capital city of the Mazandaran province, north of Iran. The study sample included patients with end-stage renal disease (ESRD) receiving outpatient hemodialysis treatment. Considering 10% attrition, 70 registered patients were randomly categorized into intervention and control groups. The proposed intervention included playing of relevant educational video tracks, conducting eight cognitive behavioral therapy (CBT) group sessions, and telephone-based peer support. Data were collected applying a set of questionnaires including sociodemographic, Beck Depression Inventory (BDI-SF), Multidimensional Scale of Perceived Social Support (MSPSS), Patient Satisfaction with Nursing Care Quality Questionnaire (PSNCQQ), End-Stage Renal Disease Adherence Questionnaire (ESRD-AQ) and the World Health Organization Quality of Life (WHOQOL-SF) scale. Sociodemographic and clinical data were collected at baseline in both groups and the postintervention assessment was performed in the intervention and nonintervention groups after one month and three months. Results: A significant change in the self-reported depression symptoms (P=0.001), mean social support score (P=0.001), nursing care satisfaction score (P=0.001), quality of life score (P=0.001) and interdialytic weight gain (IDWG) (P=0.001) was observed among the participants in the intervention group compared to the baseline measures. The highest rise in the ESRD-AQ scores within the intervention group was observed after one month of intervention (mean difference=131.88) compared to the baseline values. Same pattern of statistically significant changes in mean scores of the intervention group's attendants in all subscales of the ESRD-AQ were also ascertained. Conclusion: This interventional study revealed that inaugurating of a feasible low-cost intervention without need to add major logistic or financial inputs into existing health-care systems, especially in resource limited contexts, is achievable. Findings of this study could provide insights into scientific basis of evidence-informed interventions applicable in the realm of health-care delivery.