Abstract Background and Aims Frequency of hemodialysis is still a debatable topic. Incremental hemodialysis has gained popularity and requires a smooth increase in dialysis frequency while maintaining a sufficient residual diuresis. In developing countries and some developed countries, a twice-weekly schedule independent of residual kidney function is still performed, sometimes because of lack of resources and some other times because of patients’ resistance to undergo three sessions per week. This study aimed to compare the survival of patients on twice versus thrice-weekly hemodialysis. Method This is a prospective, multicenter, non-randomized trial, that included incident patients on chronic hemodialysis between January 2018 and August 2021. Patients terminally ill were excluded. Patients were divided into two arms: twice-weekly and thrice-weekly hemodialysis. CASTOR eCRF (electronic case report form) was used for data capture. Demographics, comorbidities, laboratory tests, medications, residual diuresis and dialysis prescription were collected from the patients' medical records at dialysis initiation. Patients were followed at 1 month, 3 months, 6 months, one year and two years for their mortality, hospitalisations for pulmonary edema or hyperkalemia, uncontrolled severe hypertension and erythropoietin (EPO) dose requirement. This trial was terminated before reaching the required sample size of 800 because of the pandemic and economic crisis in the country. Missing baseline factors and covariates were imputed using multiple imputation algorithms, then entered in a logistic regression model to estimate propensity scores. A survival analysis with a cox-regression model including propensity score as a covariate assessed the difference between twice-weekly and thrice-weekly dialysis. This trial was registered on Clinicaltrials.gov ID NCT03415776. Results A total of 203 consecutive patients of 10 dialysis units were included, 133 in the thrice-weekly arm and 70 in the twice-weekly. Mean age was 67 ± 15 years, 54.2% were males, 55.5% had diabetes, 53.7% had coronary artery disease. Median eGFR at dialysis initiation was 6 (4, 8) mL/min/1.73 m2. Baseline median 24-hour diuresis was 500 (500, 1000) mL with higher diuresis in patients on twice-weekly (P = 0.051). Baseline mean hemoglobin was 9.6 ± 1.6 g/dL. 41.7% were initiated with AV fistula with more patients in the thrice-weekly initiated with temporary catheter. Median number of dialysis hours per week was 12 (10, 12) and 8 (8, 9) in thrice- and twice-weekly respectively. High-flux membranes with ultrapure dialysate were used in 55% of thrice-weekly and 74.3% of twice-weekly. Mean blood flow was 329 ± 76 mL/min. In univariate analysis, residual diuresis was significantly higher in twice-weekly at 1 month, 3 months (P = .002), 6 months (it dropped at 6 months to a median of 100 (0, 500) in thrice-weekly versus 225 (175, 875) in twice-weekly) and at one year (P = .015). Inter-dialytic weight gain and blood pressure levels were not statistically different at 1, 3, 6 months and one year. 22.5% of patients on thrice-weekly did not need antihypertensive medications at 6 months versus 12.1% in the twice-weekly. Serum potassium was significantly higher in twice-weekly at 3 months and at one year. Cumulative dose of EPO administered during 2 years was significantly higher in twice-weekly with a median of 720000 UI versus 500000 UI in thrice-weekly (P = .001) without a difference in hemoglobin but lower ferritin in twice-weekly (P = .005). There was no difference in hospitalisations' rates between the two arms. A cox regression model including propensity scores as a covariate did not show any survival difference between the two arms (Fig. 1). Conclusion Patients on twice-weekly hemodialysis had a similar survival and hospitalisations' rates at two years as patients on thrice-weekly hemodialysis. However, a twice-weekly schedule was accompanied with higher EPO dose requirements, higher serum potassium levels, more antihypertensive therapy despite more preserved residual diuresis.