Long-duration spaceflight results in a loss of muscle strength that poses both operational and medical risks, particularly during emergency egress, upon return to Earth, and during future extraterrestrial exploration. Isokinetic testing of the knee, ankle, and trunk quantifies movement-specific strength changes following spaceflight and offers insight into the effectiveness of in-flight exercise countermeasures. We retrospectively evaluated changes in isokinetic strength for 37 ISS crewmembers (Expeditions 1–25) following 163 +/- 38 d (mean +/- SD) of spaceflight. Gender, in-flight resistance exercise hardware, and preflight strength were examined as potential modifiers of spaceflight-induced strength changes. Mean isokinetic strength declined 8–17% following space ight. One month after return to Earth, strength had improved, but small defcits of 1–9% persisted. Space flight-induced strength losses were not different between men and women. Mean strength losses were as much as 7% less in crewmembers who flew after the Advanced Resistive Exercise Device (ARED) replaced the interim Resistive Exercise Device (iRED) as the primary in-flight resistance exercise hardware, although these differences were not statistically significant. Absolute and relative preflight strength were moderately correlated (r= -0.47 and -0.54, respectively) with post flight strength changes. In-flight resistance exercise did not prevent decreased isokinetic strength after long-duration spaceflight. However, continued utilization of ARED, a more robust resistance exercise device providing higher loads than iRED, may result in greater benefits as exercise prescriptions are optimized. With reconditioning upon return to Earth, strength is largely recovered within 30 d.