Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 ± 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 ± 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 ± 12.2 vs. 153.4 ± 12.1 g, P = 0.81). Mean wall thickness decreased (4 ± 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 ± 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 ± 2.7% (P = 0.06) and RV end-diastolic volume by 16 ± 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 ± 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.