Over the past decade, membrane contactors (MBC) for CO2 absorption have been widely recognized for their large intensification potential compared to conventional absorption towers. MBC technology uses microporous hollow-fiber membranes to enable effective gas and liquid mass transfer, without the two phases dispersing into each other. The main contribution of this paper is the development and verification of a predictive mathematical model of high-pressure MBC for natural gas sweetening applications, based on which model-based parametric analysis and optimization can be conducted. The model builds upon insight from previous modeling studies by combining 1-d and 2-d mass-balance equations to predict the CO2 absorption flux, whereby the degree of membrane wetting itself is calculated from the knowledge of the membrane pore-size distribution. The predictive capability of the model is tested for both lab-scale and pilot-scale MBC modules, showing a close agreement of the predictions with measured CO2 absorption fluxes at various gas and liquid flowrates, subject to a temperature correction to account for the heat of reaction in the liquid phase. The results of a model-based analysis confirm the advantages of pressurized MBC operation in terms of CO2 removal efficiency. Finally, a comparison between vertical and horizontal modes of operation shows that the CO2 removal efficiency in the latter can be vastly superior as it is not subject to the liquid static head and remediation strategies are discussed.