The aim of this investigation was to document the exercise program used by crewmembers (n = 9; 45 ± 2 yr) while aboard the International Space Station (ISS) for 6 mo and examine its effectiveness for preserving calf muscle characteristics. Before and after spaceflight, we assessed calf muscle volume (MRI), static and dynamic calf muscle performance, and muscle fiber types (gastrocnemius and soleus). While on the ISS, crewmembers had access to a running treadmill, cycle ergometer, and resistance exercise device. The exercise regimen varied among the crewmembers with aerobic exercise performed ∼5 h/wk at a moderate intensity and resistance exercise performed 3–6 days/wk incorporating multiple lower leg exercises. Calf muscle volume decreased (P < 0.05) 13 ± 2% with greater (P < 0.05) atrophy of the soleus (−15 ± 2%) compared with the gastrocnemius (−10 ± 2%). Peak power was 32% lower (P < 0.05) after spaceflight. Force-velocity characteristics were reduced (P < 0.05) −20 to −29% across the velocity spectrum. There was a 12–17% shift in myosin heavy chain (MHC) phenotype of the gastrocnemius and soleus with a decrease (P < 0.05) in MHC I fibers and a redistribution among the faster phenotypes. These data show a reduction in calf muscle mass and performance along with a slow-to-fast fiber type transition in the gastrocnemius and soleus muscles, which are all qualities associated with unloading in humans. Future long-duration space missions should modify the current ISS exercise prescription and/or hardware to better preserve human skeletal muscle mass and function, thereby reducing the risk imposed to crewmembers.