A mathematical model has been developed to characterize the multi-component CO2capture from naturalgas 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 processsimulator to constitute the entire CO2/natural gas separation plant in order to assist in the process designand optimization. The study of the separation performance and process economics of the different flowmechanisms has been conducted along with parameter sensitivity of typical membrane selectivity andCO2feed composition in industrial application. Based on the study’s findings, ideally the countercurrentconfiguration 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 separativeperformance is not always the most economical. Under circumstances of excessive permeation, it canlead to extra membrane area, auxiliary equipment power and hydrocarbon lost that increase the gasprocessing cost. Therefore, a tradeoff must be determined among these parameters to determine theoptimal flow configuration for efficient CO2removal under different operating conditions.