A mathematical model has been developed to characterize the multi-component CO2 capture from natural gas adapting hollow fiber membrane module for the radial crossflow, countercurrent and cocurrent flow. The solution procedure can also be incorporated in a versatile manner within the Aspen HYSYS process simulator to constitute the entire CO2/natural gas separation plant in order to assist in the process design and optimization. The study of the separation performance and process economics of the different flow mechanisms has been conducted along with parameter sensitivity of typical membrane selectivity and CO2 feed composition in industrial application. Based on the study's findings, ideally the countercurrent configuration exhibits a slightly higher separative performance in comparison to the radial crossflow, while both being superior to the cocurrent. It is also found that flow with the most effective separative performance is not always the most economical. Under circumstances of excessive permeation, it can lead to extra membrane area, auxiliary equipment power and hydrocarbon lost that increase the gas processing cost. Therefore, a tradeoff must be determined among these parameters to determine the optimal flow configuration for efficient CO2 removal under different operating conditions. © 2015 Elsevier Ltd.