Tolerance to +G_z gravitational stress is reduced when +G_z stress is preceded by exposure to hypogravity (fraction, 0, or negative G_z). For example, there is an exaggerated fall in eye-level arterial pressure (ELAP) early-on during +G_z stress (head-up tilt; HUT) when this stress is immediately preceded by -G_z stress (head-down tilt; HDT). We sought to characterize the hemodynamic consequences of brief HDT on subsequent HUT and to test the hypothesis that an elevation in leg vascular conductance induced by -G_z stress contributes to the exaggerated fall in ELAP. Young, healthy subjects (n = 3 males and 4 females) were subjected to 30 s of 30° HUT from a horizontal position and to 30 s of 30° HUT when HUT was immediately preceded by 20 s of -15° HDT. Brief exposure to HDT elicited an exaggerated fall in ELAP during the first few seconds of the subsequent HUT (-17.9 ±1.4 mmHg) compared to HUT alone (-12.4 ±1.2 mmHg, p <0.05) despite a greater rise in stroke volume and cardiac output over this brief time period in the HDT-HUT trials compared to the HUT trials (thereafter stroke volume fell under both conditions). The greater fall in ELAP was associated with an exaggerated increase in leg blood flow and was therefore largely (70%) attributable to an exaggerated rise in estimated leg vascular conductance, confirming our hypotheses. Thus, brief exposure to -G_z stress leads to an exaggerated fall in ELAP during subsequent HUT owing to an exaggerated increase in estimated leg vascular conductance.