The use of flip-chip technology has many advantages over other approaches for high-density electronic packaging. ACF (anisotropic conductive film) is one of the major flip-chip technologies, which has short chip-to-chip interconnection length, high productivity, and miniaturization of package. In this study, thermal fatigue lift of ACF bonding flip-chip package has been predicted. Elastic and thermal properties of ACF were measured by using DMA and TMA. Temperature dependent nonlinear hi-thermal analysis was conducted and the result was compared with Moire interferometer experiment. Calculated displacement field was well matched with experimental result. Thermal fatigue analysis was also conducted. The maximum shear strain occurs at the outmost located bump. Shear stress-strain curve was obtained to calculate fatigue life. Fatigue model for electronic adhesives was used to predict thermal fatigue life of ACF bonding flip-chip packaging. DOE (Design of Experiment) technique was used to find important design factors. The results show that PCB CTE (Coefficient of Thermal Expansion) and elastic modulus of ACF material are important material parameters. And as important design parameters, chip width, bump pitch and bump width were chose. 2$^{nd}$ DOE was conducted to obtain RSM equation far the choose 3 design parameter. The coefficient of determination ($R^2$) for the calculated RSM equation is 0.99934. Optimum design is conducted using the RSM equation. MMFD (Modified Method for feasible Direction) algorithm is used to optimum design. The optimum value for chip width, bump pitch and bump width were 7.87mm, 430$mu$m, and 78$mu$m, respectively. Approximately, 1400 cycles have been expected under optimum conditions. Reliability analysis was conducted to find out guideline for control range of design parameter. Sigma value was calculated with changing standard deviation of design variable. To acquire 6 sigma level thermal fatigue reliability, the Std. Deviation of design parameter should be controlled within 3% of average value.