Standard Kt/V(urea) (stdKt/V) is a hypothetical continuous clearance in patients treated with intermittent hemodialysis based on the generation rate of urea nitrogen and the average predialysis urea nitrogen. Previous equations to estimate stdKt/V were derived using a fixed-volume model. To determine the impact of fluid removal as well as residual urea clearance on stdKt/V, we modeled 245 hemodialysis sessions (including conventional 3/week, in-center 6/week, and at-home nocturnal 6/week) in 210 patients enrolled in the Frequent Hemodialysis Network Daily and Nocturnal clinical trials. To examine the role of fluid removal, modeled stdKt/V was compared to stdKt/V estimated from a previously published simplified equation. In a subgroup of 45 sessions with residual urea clearance over 1.5 ml/min, the contribution of residual urea clearance to stdKt/V was measured. For all dialysis schedules, the fixed-volume equation predicted stdKt/V well when both fluid removal and residual urea clearance were set to zero. When fluid removal was included, modeled stdKt/V was slightly underestimated for all three modes of hemodialysis. The shortfall correlated directly with weekly fluid removal and inversely with modeled urea volume. Modeled stdKt/V compressed residual urea clearance to about 70% of its measured value and the fractional downsizing significantly correlated inversely with treatment Kt/V. Our new equation predicted modeled stdKt/V with a high level of accuracy, even when substantial fluid removal and residual urea clearance were present.