The delicate interplay between the muscle-joint unit and intact venous valves is mandatory for normal venous blood return from the human leg. We have investigated the potential role of (1) muscle activity and joint mobility, and (2) anthropometric factors for peripheral venous pressure physiology. 20 healthy young subjects (10 males, 10 females; mean age: 25.6 ± 3.1 years) underwent direct venous blood pressure measurements during walking on a treadmill in 12 experimental conditions (duration, 1 min each): these resulted from a combination of two different walking velocities, two different degrees of ascent, and three different walking conditions. Anthropometric parameters (e.g., body height, weight and calf circumference) were also measured in all subjects. Outcome measures were the pressures (mm Hg) during quiet standing (resting pressure, P₀), the maximal activity-induced pressure reduction (ΔP<sub>max</sub>), i.e., the difference between the resting pressure (P₀) and minimal pressure during exercise (P<sub>min</sub>), the times (s) to minimal pressure during exercise (T<sub>Pmin</sub>) and to half-maximal recovery of P₀ after exercise (T<sub>max1/2</sub>). We found that the maximal venous pressure reduction (ΔP<sub>max</sub>) during walking increased at the higher walking speed and decreased with restricted joint mobility (p = 0.0001). Taller and heavier subjects, or subjects with a greater calf circumference had higher P₀ (p = 0.0001), showed greater ΔP<sub>max</sub> (p < 0.010), and took longer to achieve minimal pressure during exercise (T<sub>Pmin</sub>; p < 0.010) than their corresponding counterparts. Females had lower levels of P₀ (p = 0.0001), but not of ΔP<sub>max</sub>, and shorter T<sub>Pmin</sub> (p = 0.0076) than males. These gender effects largely result from differences in body height, weight, and calf circumference (p = 0.0001 for the appropriate ANOVA interaction terms). We conclude that during walking, a higher degree of muscle activity and a greater muscle mass enhance venous emptying of the healthy human leg. Conversely, impairments of joint mobility reduce the efficacy of the muscle-vein pump. Moreover, body height and weight significantly influence venous pressure physiology under both resting and activity-related conditions. These anthropometric factors also largely explain sex differences in peripheral venous hemodynamics.