In post-thrombotic and May-Thurner syndromes, the iliac veins may be scarred, compressed, or obstructed. Obesity and increased intra-abdominal pressure may also hamper the venous return. Therefore, measurements of outflow resistance (OR) impeding venous return may be helpful to select patients for intervention and to assess the impact of intervention. A proof-of-concept study is presented in healthy volunteers where OR is quantified using duplex assessment of the femoral vein (FV) at mid-thigh following predetermined inflation pressures with a high thigh tourniquet. Twenty-two consecutive subjects (15 male) without evidence of venous disease by clinical and duplex examination were studied. Two male exclusions were due to bifid FVs. Median (range) baseline characteristics were age 30years (24-57years), height 173cm (158-197cm), weight 72kg (50-97kg), leg length 80cm (74-94cm), and FV diameter 11.2mm (6.8-14.8mm). Subjects were examined standing with the test leg nonweight-bearing, resting gently on the floor. A 26-cm-wide calf cuff was attached to an intermittent pneumatic compression device that delivered three compressions per minute at 120mm Hg. A high thigh cuff, 12cm wide, was inflated just before each calf compression in multiples of 20mm Hg, from 0 to 120mm Hg, to provide a standard OR. FV waveform parameters were recorded using duplex beneath each thigh-cuff inflation pressure and repeated three times. OR was calculated using change in pressure (P2-P1)/Flow (Q). Pressure P2 was 120mm Hg minus the additional height to the duplex transducer. P1 was assumed tobe zero. Flow was cross-sectional area (π× diameter [d](2)/4)× velocity. The velocity parameters chosen were peakvelocity (PV), time-averaged mean velocity (TAMV), andTAMV from start to peak. Peak velocity, TAMV, and TAMV to peak all decreased significantly (P< .0005; Friedman) with increasing thigh cuff pressure with P< .0005 correlations (Spearman) of r= .842, r= .488, and r= .744, respectively. Furthermore, increasing thigh cuff pressure at 0, 20, 40, 60, 80, 100, and 120mm Hg also caused a gradual and significant increase in median (interquartile range) OR at 27 (19-34), 30 (21-42), 30 (23-44), 40 (26-47), 46 (32-51), 61 (38-71), and 79 (45-134) resistance units, respectively (P< .0005; Friedman, and r= .516; Spearman). Higher baseline (innate) OR values were found in taller (P= .002) and heavier (P= .043) subjects. Hemodynamic velocity parameters in the femoral vein attenuate progressively with increasing venous obstruction. Outflow resistance (OR) can be quantified using duplex measurements when they are substituted into equations of fluid mechanics. Optimization of this novel technique, which requires an IPC outflow challenge test, may provide useful information in the assessment and treatment of patients.