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Objectives:. The time course and magnitude of atrophic remodeling and the effects of an acute rehabilitation program on muscle atrophy are unclear. We sought to characterize bed rest–induced leg muscle atrophy and evaluate the safety and efficacy of an acute rehabilitation program. Design:. Prespecified analysis of a randomized controlled trial. Setting:. Single-center urban hospital. Patients:. Adults (24–55 yr) randomized to 70 days of sedentary bed rest. Interventions:. The 11-day post-bed rest rehabilitation program consisted of low intensity exercise and progressed to increased aerobic exercise duration, plyometric exercises, and higher intensity resistance exercise. Measurements and Main Results:. Upper (rectus femoris, vastus lateralis, quadriceps, hamstrings, adductors) and lower leg (medial gastrocnemius, lateral gastrocnemius, and soleus) MRI scans were obtained once before, nine times during, and three times after bed rest to assess muscle cross-sectional area. The magnitude and rate of muscle atrophy and recovery were determined for each muscle. Nine participants completed 70 days of sedentary bed rest and an 11-day rehabilitation program. A total of 11,588 muscle cross-sectional area images were quantified. Across all muscles except the rectus femoris (no change), there was a linear decline during bed rest, with the highest atrophic rate occurring in the soleus (–0.33%/d). Following rehabilitation, there was rapid recovery in all muscles; however, the quadriceps (–3.74 cm2; 95% CI, –7.36 to –0.12; p = 0.04), hamstrings (–2.30 cm2; 95% CI, –4.07 to –0.54; p = 0.01), medial gastrocnemius (–0.62 cm2; 95% CI, –1.10 to –0.14; p = 0.01), and soleus (–1.85 cm2; 95% CI, –2.90 to –0.81; p < 0.01) remained significantly lower than baseline. Conclusions:. Bed rest results in upper and lower leg muscle atrophy in a linear pattern, and an 11-day rehabilitation program was safe and effective in initiating a rapid trajectory of muscle recovery. These findings provide important information regarding the design and refinement of rehabilitation programs following bed rest.