In this study, a computational fluid dynamic (CFD) model was developed to simulate the liquid cone-jet and core-shell droplet formation in the Coaxial Electrohydrodynamic Atomization (CEHDA) process. Validation experiments were conducted using poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) solutions as core and shell materials, respectively. Good agreement was obtained between experimental results and simulation predictions in terms of both particle size and core-shell structure. Investigation of interfacial tension between core and shell fluids showed that a stable compound cone-jet and droplet can be easily formed using miscible or partially miscible liquids compared with immiscible liquids with higher interfacial tension. It was also found that the nozzle tip configuration has significant effects on droplet production due to differences in fluid motion. The results also showed that the productivity of the CEHDA process, that is, slow production of core-shell microparticles due to low flow rates, could be enhanced using optimal cone-shaped nozzle configuration. Overall, this computational model provided a means of designing and optimizing CEHDA processes for large-scale core-shell microparticle fabrication in pharmaceutical application, such as selections of materials and nozzle configuration. (c) 2016 American Institute of Chemical Engineers AIChE J, 62: 4259-4276, 2016