The novel Capiox NX19 adult oxygenator is, compared to its predecessors, improved with enhanced air removal technology, a polymer heat exchanger and smaller, innovative hollow fibers resulting in a surface area reduction and a lower priming volume. The aim of this study was to evaluate the NX19 oxygenator performance in a clinical setting. A prospective multicenter study was performed involving three large European university hospitals. The Capiox NX19 (n = 150) performance was assessed during adult cardiopulmonary bypass and involved gaseous microemboli handling and gas transfer efficiency. The heat exchanger performance was evaluated separately in vitro. The heat exchanger performance factors were 0.80 ± 0.03 and 0.58 ± 0.04 at pump flow rates of 3 L/min and 6 L/min, respectively. After priming, residual post-oxygenator gaseous microemboli count and volume were decreased by 91% and 93.7%, respectively. The gas compartment pressure was 6.0 ± 2.5 mmHg, while the O2 transfer was 69 ± 30 mL/min/m2 and the CO2 transfer 73 ± 34 mL/min/m2. The O2 gradient was 44 ± 19 mmHg/LPM and the O2 diffusing capacity 0.38 ± 0.14 mL/min/mmHg. The shunt fraction was 0.19 ± 0.13, whereas oxygenator resistance and shear stress were 10.5 ± 3.7 mmHg/LPM and 5.1 ± 3.1 dyn/cm2, respectively. This multicenter study displayed good clinical safety and performance of the NX19 oxygenator.