This study hypothesized that central and local reflex mechanisms affecting vascular conductance (VC) through the popliteal artery compensated for the reduction in muscle perfusion pressure (MPP) to maintain popliteal blood flow (PBF) during head-down tilt (35˚ HDT), but not in head-up tilt (45˚ HUT). Resting measurements were made on 15 healthy men in prone position to facilitate the access to the popliteal artery, on two separate days in random order during horizontal (HOR), HDT or HUT. In each body position, the body was supported, and the ankles were maintained in relaxed state so that there was no muscle tension, as with normal standing. Popliteal blood flow velocity and popliteal arterial diameter were measured by ultrasound, and PBF was calculated. MPP was corrected to mid-calf from measured finger cuff pressure, and VC was estimated by dividing PBF by MPP. The MPP in HDT (48 ± 2 mmHg) was ~100mmHg less than in HUT (145 ± 2 mmHg). PBF was similar between HOR (51 ± 18 ml min−1) and HDT (47 ± 13 ml min−1), but was lower in HUT (30 ± 9 ml min−1). VC was different between HDT (1·0 ± 0·3 ml min−1 mmHg−1), HOR (0·6 ± 0·2 ml min−1 mmHg−1) and HUT (0·2 ± 0·1 ml min−1 mmHg−1). In conclusion, the interactions of central and local regulatory mechanisms resulted in a disproportionate reduction of VC during HUT lowering PBF even though MPP was higher, while in HDT, increased VC contributed to maintain PBF at the same level as the HOR control condition.