INTRODUCTION: The aim was to study quadriceps muscle activation during resistance exercise using a flywheel device, developed as a gravity-independent resistance exercise device to be used during spaceflight, compared with traditional strength training exercises. METHODS: Eight healthy men experienced in resistance exercise performed the following exercises in random order: flywheel leg press (FW), knee extension isokinetic dynamometry (ID), barbell front squat (FS), weight stack leg press (LP), and weight stack knee extension (KE). They accomplished eight repetitions of coupled concentric and eccentric actions with simultaneous recordings of surface electromyography (EMG) from the three superficial quadriceps muscles and knee angles using electrogoniometry. Maximal voluntary contraction (MVC) in knee extension was performed before and after these measurements. RESULTS: EMG averaged across muscles and angles and normalized to MVC was 99/76% in FW, 48/41% FS, 65/47% LP, 81/52% KE, and 93/84% ID in concentric/eccentric phases, respectively. FW and ID showed higher mean EMG activity than LP and FS concentrically and higher than all other exercises eccentrically. No difference in activity between FW and ID was found. Pre- and post-MVC torque was comparable. DISCUSSION: Quadriceps muscle activation was superior in FW and ID exercises compared to the other exercises. The difference was most pronounced in the eccentric phase, but even concentric activation was lower in traditional closed chain exercises. This data supports that FW is an effective training tool and should be considered when designing strength training programs for spaceflights and on Earth.