Mitchinson, CJ, Best, S, Caruso, J, and Bollinger, LM. Cardiorespiratory responses to flywheel-based inertial training squats with varying moments of inertia. J Strength Cond Res 39(3): 300-306, 2025-Flywheel-based inertial training (FIT) has gained popularity as a means to enhance muscle hypertrophy. Other applications, such as aerobic exercise training, remain unexplored. The aim of this study was to determine the cardiorespiratory responses to acute FIT with varying moments of inertia (MOIs). Overall, 20 (10 M, 10 F) healthy, physically active subjects underwent maximal graded exercise testing and completed 3 bouts of FIT exercise (1 familiarization session and 2 identical data collection sessions). Subjects completed quarter squats (60° peak knee flexion) at a pace of 50 squats·minute -1 until volitional fatigue. Flywheel-based inertial training MOI was increased by 0.005 kg·m 2 every 3 minutes until a final workload of 0.020 kg·m 2 . Heart rate and gas exchange data were collected continuously and averaged over the final 60 s of each stage. Data were analyzed by a linear mixed model. During the final testing session, there was a main effect of MOI to increase heart rate (HR), V̇ o2 , and RER. Men displayed greater oxygen consumption, but a similar %V̇ o2 peak compared with women. We noted a significant inertia × sex interaction where RER tended to be lesser in women at higher MOI. In the final stage of exercise (MOI: 0.020 kg·m 2 ), HR and V̇ o2 were approximately 75-80 and 55% of peak, respectively, and RER was approximately 0.95-1.00. FIT quarter squats elicit moderate HR and V̇ o2 responses, but near-maximal RER suggests a novel metabolic training stimulus. This exercise may supersede the lactate threshold and may not be sustainable for prolonged times. The physiological and performance effects of training in this manner are unclear.