The vast majority of quantitative data examining the effects of breathing on venous return have been derived from anaesthetized or reduced animal preparations, making an extrapolation to an upright exercising human problematic due to the lack of a hydrostatic column and an absence of muscular contraction. Thus, this study is the first to quantitatively examine the effects of different breathing mechanics on venous return from the locomotor limbs both at rest and during calf contraction exercise in the semirecumbent human. When subjects inspired using predominantly their ribcage/accessory inspiratory muscles at rest (change in gastric pressure (DeltaP(GA)) = <2 cmH(2)O, change in oesophageal pressure (DeltaP(ES)) = approximately -6 cmH(2)O; inspiratory time/total breath time (T(I)/T(TOT)) = 0.5), a slight facilitation of femoral venous return was observed during inspiration (65% of all flow occurred during inspiration), with a slight reduction in femoral venous return during the ensuing expiratory phase of the breath. However, when subjects inspired using a predominantly diaphragmatic breath at rest (DeltaP(GA) = > 5 cmH(2)O, DeltaP(ES) = approximately -6 cmH(2)O; T(I)/T(TOT) = 0.5), femoral venous return was markedly impeded (net retrograde flow of 11%) and significantly lower than that observed during ribcage breathing conditions (P < 0.01). During the ensuing expiratory phase of a diaphragmatic breath, there was a large resurgence of femoral venous blood flow. The pattern of modulation during ribcage and diaphragmatic breathing persisted during both mild (peak calf force = 7 kg) and moderate (peak calf force = 11 kg) levels of calf contraction. Despite the significant within-breath modulation of femoral venous return by breathing, net blood flow in the steady state was not altered by the breathing pattern followed by the subjects. Though popliteal blood flow appeared to be modulated by respiration at rest, this pattern was absent during mild calf contraction where popliteal outflow was phasic with the concentric phase of calf contraction. We conclude that respiratory muscle pressure production is the predominant factor modulating venous return from the locomotor limb both at rest and during calf contraction even when the veins of the lower limb are distended due to the presence of a physiologic hydrostatic column.