This paper describes a study of solder joint reliability of a copper column (CuC) interconnect scheme in wafer level packages using a simulation-based design optimization methodology to investigate the effects of various design parameters on the solder joint thermo-mechanical reliability and to find the optimal parameter settings. Design of experiments (DoE), surrogate modeling and numerical optimization techniques, together with computer simulation have been integrated in this approach. Four design parameters are involved in this study, namely the chip thickness, substrate thickness, substrate CTE, and CuC height. A full factorial DoE method is adopted to prescribe the required simulation runs. The incremental equivalent plastic strain will serve as the indicator of solder joint thermo-mechanical reliability By applying this simulation-based design optimization approach, the effects of various parameters are identified and an optimal parameter setting is determined.