ABSTRACT: RATIONALE & OBJECTIVE:Patients receiving twice-weekly or less-frequent hemodialysis (HD) may need to undergo higher ultrafiltration rates (UFRs) to maintain acceptable fluid balance. We hypothesized that higher UFRs are associated with faster decline in residual kidney function (RKF) and a higher rate of mortality. STUDY DESIGN:Retrospective cohort study. SETTING & PARTICIPANTS:1,524 patients with kidney failure who initiated maintenance HD at a frequency of twice or less per week for at least 6 consecutive weeks at some time between 2007 and 2011 and for whom baseline data for UFR and renal urea clearance were available. PREDICTOR:Average UFR during the first patient-quarter during less-frequent HD (<6, 6-<10, 10-<13, and?13mL/h/kg). OUTCOME:Time to all-cause and cardiovascular death, slope of decline in RKF during the first year after initiation of less-frequent HD (with slopes above the median categorized as rapid decline). ANALYTICAL APPROACH:Cox proportional hazards regression for time to death and logistic regression for the analysis of rapid decline in RKF. RESULTS:Among 1,524 patients, higher UFR was associated with higher all-cause mortality; HRs were 1.43 (95% CI, 1.09-1.88), 1.51 (95% CI, 1.08-2.10), and 1.76 (95% CI, 1.23-2.53) for UFR of 6 to<10, 10 to<13, and?13mL/h/kg, respectively (reference: UFR < 6mL/h/kg). Higher UFR was also associated with higher cardiovascular mortality. Baseline RKF modified the association between UFR and mortality; the association was attenuated among patients with renal urea clearance?5mL/min/1.73m2. Higher UFR had a graded association with rapid decline in RKF; ORs were 1.73 (95% CI, 1.18-2.55), 1.89 (95% CI, 1.12-3.17), and 2.75 (95% CI, 1.46-5.18) at UFRs of 6 to<10, 10 to<13, and?13mL/h/kg, respectively (reference: UFR < 6mL/h/kg). LIMITATIONS:Residual confounding from unobserved differences across exposure categories. CONCLUSIONS:Higher UFR was associated with worse outcomes, including shorter survival and more rapid loss of RKF, among patients receiving regular HD treatments at a frequency of twice or less per week.