Respiration and the muscle pump play major roles in increasing venous return. However, the relative contribution of each of these factors remains unclear. The present study investigates the quantitative effects of interaction between respiration and the muscle pump on femoral venous blood flow (FVBF) during a single voluntary knee extension-flexion (KEF) using duplex-Doppler ultrasound. During various respiration modes, which consisted of arrested respiration, normal respiration and deep respiration (inspiration or expiration), eight subjects performed a supine one-legged voluntary KEF. FVBF was measured during respiration only (Protocol A) and during KEF synchronized with respiration (Protocol B). The difference between FVBF values obtained in Protocol B and Protocol A was defined as DeltaFVBF. When KEF was synchronized with normal or deep respiration, FVBF with inspiration was significantly lower than that with expiration. However, DeltaFVBF was significantly higher with inspiration than with expiration during deep respiration but was not significant during normal respiration. Furthermore, DeltaFVBF was significantly higher at both normal and deep respiration than at arrested respiration. The effects upon the venous return during KEF differed between inspiration and expiration. The present findings indicate that during a single supine KEF, respiration might promote venous return to a range of 1.5- to 2.3-fold DeltaFVBF during arrested respiration.