Oxygenators take over lung function in the event of severe lung injuries by exchanging gas into the blood stream using hollow fiber membrane mats. A central limitation of oxygenators is their large foreign surface area and priming volume, which cause blood damage.Thus, gas exchange efficiency needs to be improved through an understanding of the interaction between fiber arrangement and blood flow directions. This has only been investigated in two dimensional or simplified non-realistic fiber bundles. The aim of this study was to quantify gas exchange in realistic 3D fiber bundles.We performed three dimensional micro scale CFD simulations of different realistic fiber arrangements and flow directions that we validated in corresponding test oxygenators using porcine blood.Fiber-configurations influence gas transfer by factor 2, with highest transfer rates for blood flowing in circumferential direction, and lowest for longitudinal direction in wound oxygenators. The CFD model correlates with the experiments with an R2 = 0.88.For the first time, the configuration of realistic 3D fiber bundles was proven to strongly influence gas transfer in oxygenators, in simulations and experiments. The CFD model serves for investigation of further configurations and to derive transfer coefficients for full scale oxygenators.