The correct calculation of cell void fraction is pivotal in accurate simulation of two-phase flows using a computational fluid dynamics-discrete element method (CFD-DEM) approach. Two classical approaches for void fraction calculations (i.e., particle centroid method or PCM and analytical approach) were examined, and the accuracy of these methodologies in predicting the particle-fluid flow characteristics of bubbling fluidized beds was investigated. It was found that there is a critical cell size (3.82 particle diameters) beyond which the PCM can achieve the same numerical stability and prediction accuracy as those of the analytical approach. There is also a critical cell size (1/19.3 domain size) below which meso-scale flow structures are resolved. Moreover, a lower limit of cell size (1.63 particle diameters) was identified to satisfy the assumptions of CFD-DEM governing equations. A reference map for selecting the ideal computational cell size and the suitable approach for void fraction calculation was subsequently developed. (c) 2014 American Institute of Chemical Engineers AIChE J, 60: 2000-2018, 2014