The operating temperature of power semiconductor devices is one of the limiting factors that affects the overall reliability performance of the power electronic system. Therefore, an accurate thermal loading estimation is required for realistic reliability prediction of power electronics. However, the thermal analysis is typically performed based on rough approximations of the thermal impedance characteristic, which is provided by the manufacturer in the device datasheet. In this paper, the uncertainties introduced by the variation of IGBT thermal impedance on the lifetime prediction of a motor drive IGBT module are investigated and quantified. Thus, a better understanding of the underlying assumptions of the reliability estimation procedure and of the error margins introduced by the thermal modeling of power devices can be acquired. An analytical mission-profile-based reliability assessment methodology is used to quantify the impact of unevenly distributed IGBT thermal impedance on the power module wear-out failure under three different scenarios (e.g., realistic, worst-case, and best-case).