INTRODUCTION: The current exercise countermeasures have not fully protected astronauts' preflight aerobic and muscular fitness levels during International Space Station (ISS) missions, prompting a need to optimize the exercise prescription to improve or maintain astronauts' ability to perform critical tasks and eventually extend the duration of missions. PURPOSE: To test the hypothesis that an integrated resistance and aerobic exercise prescription performed with exercise equipment similar to that on the ISS can be tolerated and maintain cardiovascular and muscular fitness during 14 d of exposure to a model of microgravity. METHODS: Subjects (n = 9) participated in 14-21 d of pre-bed rest training and familiarization, 14 d of bed rest + iRAT exercise, and 7 d of ambulatory recovery. Peak aerobic capacity (VO2peak), ventilatory threshold (VT), and isokinetic and leg press tests were performed before and after bed rest to evaluate cardiovascular and muscle functions. Muscle cross-sectional area (CSA) was determined before, during, and after bed rest using magnetic resonance imaging (MRI). RESULTS: Improvements from before to after bed rest were observed in VO2peak (2.8 ± 0.2 to 3.2 ± 0.2 L·min-1), VT (1.9 ± 0.2 to 2.1 ± 0.2 L·min-1), leg muscle power (1582 ± 317 to 1740 ± 359 W), and muscle CSA of the grouped vastus lateralis, vastus intermedius, and vastus medialis muscles (67.5 ± 8.4 to 68.9 ± 8.3 cm2). Muscle strength and total CSA of the upper and lower legs were not different from before to after bed rest. CONCLUSIONS: This is the first report of exercise being completely effective for the prevention of cardiovascular and skeletal muscle deconditioning during strict bed rest using exercise equipment similar to that on the ISS. This was accomplished with high subject compliance.