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The chip-on-glass (COG) technique using anisotropic conductive film (ACF) has been developed for liquid crystal display (LCD) panels with excellent resolution and high quality for several years. However, many serious manufacturability and reliability issues were observed from previous studies. In those, delamination occurring at the ACF interface is one of the common concerns. Few works presented analysis of delamination mechanism through the whole COG bonding process with the combination of LCD module scale and ACF interconnect scale. In this paper, the delamination mechanism of COG/ACF interconnection was studied by using finite element analysis. Equivalent block and global-local modeling methods were implemented with nonlinear elastic-plastic and sequential coupled thermal-mechanical analysis. The critical parameters of the COG bonding process and geometry of integrated circuit (IC) and glass were investigated to understand the mechanism of ACF delamination. It was found that the delamination could be reduced by decreasing the temperature difference between bonding head and glass substrate or using thin and short IC. The local model analysis revealed that the interface of glass/ACF epoxy encountered the higher stress than that in the interface of IC/ACF epoxy and had the higher possibility to delaminate. Therefore, increasing the bonding-strength between glass and ACF epoxy is the direction to reduce the probability of ACF delamination.