BACKGROUND: This is the first simulation of a 14-d lunar mission including 6 d on the Moon. HYPOTHESIS: We hypothesized that a lunar gravity simulation in the middle of a head-down tilt (HDT) might result in some reversal of body fluid/hormonal responses, and influence cardiovascular deconditioning. METHODS: Six men (28 +/- 2.5 yr) were placed in bed rest (BR): in (HDT) (-6 degrees) to simulate microgravity during the travel (two 4-d periods), and in head-up tilt (HUT) (+10 degrees) (6-d period) to simulate lunar gravity (1/6 g). Muscular exercise was performed during the HUT period to simulate 6 h of lunar EVA. Heart rate variability (HRV) and hormonal responses were studied. RESULTS: An orthostatic arterial hypotension was observed after the BR (tilt test) in 4 of the 6 subjects. Plasma volume measured at D14 decreased by -11.1% (vs. D-3, sitting position). A decrease in atrial natriuretic peptide (26 +/- 3.5 pg.ml-1 (D14) vs. 37.9 +/- 3.5 pg.ml-1 (D-3, sitting) and an increase in plasma renin activity (198 +/- 9.2 mg.L-1.min-1 (D14) vs. 71 +/- 9.2 mg.L-1.min-1 (D-3, sitting) were observed during the BR, more pronounced in HUT at 7:00 p.m. Sympathetic-parasympathetic balance (HRV) at rest showed a decrease in parasympathetic indicator and an increase in sympathetic indicator in BR (p < 0.05), without differences within HDT and HUT periods. CONCLUSION: These changes were mostly similar to those reported in spaceflights, and HDT. Although the exposure to 1/6 g with exercise modified some hormonal and body fluid responses, this partial gravity simulation was not sufficient to prevent the decrease in orthostatic tolerance observed here as well as after Apollo lunar missions.