This study compared the metabolic, cardiopulmonary and inflammatory responses of novel acute machine based concentrically-focused resistance exercise (CON RX) and eccentrically-focused resistance exercise (ECC RX). Twenty healthy adults (26.8 ± 5.9 yrs; 25.4 ± 4.0 kg/m2) performed two work-matched RX exercise sessions. Cardiopulmonary responses, rating of perceived exertion (RPE), soreness, oxygen consumption; (VO2) were collected during each session. Blood lactate and levels of inflammatory cytokines interleukin-1 alpha (IL1α), interleukin-6 (IL6) and tumor necrosis factor-alpha (TNFα) were analyzed pre, post ad 24 hours post-exercise. HR were higher (5-15bpm) during ECC RX (p<.05). Soreness ratings were consistently higher post-ECC RX compared to CON RX. VO2 area under the curve was higher during ECC than CON (31,905 ml/kg/min vs 25,864 ml/kg/min; p<.0001). Post-ECC RX, TNFα levels increased compared to CON RX 23.2 ± 23.9% versus 6.3 ± 16.2% ( p=.021). ECC RX induced greater metabolic, cardiopulmonary and soreness responses compared to matched CON RX. This may be due to recruitment of additional stabilizer muscles and metabolic stress during the ECC RX. These factors should be considered when designing ECC RX programs particularly for untrained persons, older adults or those with history of cardiovascular disease.