This work presents an experimental and modelling evaluation of the preferential oxidation of CO (CO PROX) from a H2-rich gas stream typically produced from fossil fuels and ultimately intended for hydrogen fuel cell applications. A microchannel reactor containing a washcoated 8.5 wt.% Ru/Al2O3 catalyst was used to preferentially oxidise CO to form CO2 in a gas stream containing (by vol.%): 1.4% CO, 10% CO2, 18% N2, 68.6% H2, and 2% added O2. CO concentrations in the product gas were as low as 42 ppm (99.7% CO conversion) at reaction temperatures in the range 120−140 °C and space velocities in the range 65.2−97.8 NL gcat−1 h−1. For these conditions, less than 4% of the H2 feed was consumed via its oxidation and reverse water-gas shift. Furthermore, a computational fluid dynamic (CFD) model describing the microchannel reactor for CO PROX was developed. With kinetic parameter estimation and goodness of fit calculations, it was determined that the model described the reactor with a confidence interval far greater than 95%. In the temperature range 100−200 °C, the model yielded CO PROX reaction rate profiles, with associated mass transport properties, within the axial dimension of the microchannels−−not quantifiable during the experimental investigation. This work demonstrates that microchannel reactor technology, supporting an active catalyst for CO PROX, is well suited for CO abatement in a H2-rich gas stream at moderate reaction temperatures and high space velocities.