Decrements in muscular strength during long-duration missions in space could be mission-critical during construction and exploration activities. The purpose of this study was to quantify changes in muscle volume, strength, and endurance of crewmembers on the International Space Station (ISS) in the context of new measurements of loading during exercise countermeasures. Strength and muscle volumes were measured from four male ISS crewmembers (49.5 +/- 4.7 yr, 179.3 +/- 7.1 cm, 85.2 +/- 10.4 kg) before and after long-duration spaceflight (181 +/- 15 d). Preflight and in-flight measurements of forces between foot and shoe allowed comparisons of loading from 1-g exercise and exercise countermeasures on ISS. Muscle volume change was greater in the calf (-10 to 16%) than the thigh (-4% to -7%), but there was no change in the upper arm (+0.4 to -0.8%). Isometric and isokinetic strength changes at the knee (range -10.4 to -24.1%), ankle (range -4 to -22.3%), and elbow (range -7.5 to -16.7%) were observed. Although there was an overall postflight decline in total work (-14%) during the endurance test, an increase in postflight resistance to fatigue was observed. The peak in-shoe forces during running and cycling on ISS were approximately 46% and 50% lower compared to 1-g values. Muscle volume and strength were decreased in the lower extremities of crewmembers during long-duration spaceflight on ISS despite the use of exercise countermeasures. in-flight countermeasures were insufficient to replicate the daily mechanical loading experienced by the crewmembers before flight. Future exercise protocols need careful assessment both in terms of intensity and duration to maximize the "dose" of exercise and to increase loads compared to the measured levels.