We hypothesized that the association of ultrafiltration rate with mortality in hemodialysis patients was differentially affected by weight and sex and sought to derive a sex- and weight-indexed ultrafiltration rate measure that captures the differential effects of these parameters on the association of ultrafiltration rate with mortality. Data were analyzed from the US Fresenius Kidney Care (FKC) database for 1 year after patient entry into a FKC dialysis unit (baseline) and over 2 years of follow-up for patients receiving thrice-weekly in-center hemodialysis. To investigate the joint effect of baseline-year ultrafiltration rate and postdialysis weight on survival, we fit Cox proportional hazards models using bivariate tensor product spline functions and constructed contour plots of weight-specific mortality hazard ratios over the entire range of ultrafiltration rate values and postdialysis weights (W). In the studied 396,358 patients, the average ultrafiltration rate in ml/h was related to postdialysis weight (W) in kg: 3W+330. Ultrafiltration rates associated with 20% or 40% higher weight-specific mortality risk were 3W+500 and 3W+630 ml/h, respectively, and were 70 ml/h higher in men than in women. Nineteen percent or 7.5% of patients exceeded ultrafiltration rates associated with a 20% or 40% higher mortality risk, respectively. Low ultrafiltration rates were associated with subsequent weight loss. Ultrafiltration rates associated with a given mortality risk were lower in high-body weight older patients and higher in patients on dialysis for more than 3 years. Ultrafiltration rates associated with various levels of higher mortality risk depend on body weight, but not in a 1:1 ratio, and are different in men versus women, in high-body weight older patients, and in high-vintage patients.