The Light-Emitting Diode (LED) has become a very promising alternative lighting source with the advantages of longer lifetime and higher efficiency than traditional ones. The lifetime prediction of LEDs is important to guide the LED system designers to fulfill the design specifications and to benchmark the cost-competitiveness of different lighting technologies. However, the existing lifetime data released by LED manufacturers or standard organizations are usually applicable only for some specific temperature and current levels. Significant lifetime discrepancies may be seen in the field operations due to the varying operational and environmental conditions during the entire service time (i.e., mission profiles). To overcome the challenge, this paper proposes an advanced lifetime prediction method, which takes into account the field operation mission profiles and also the statistical properties of the life data available from accelerated degradation testing. The electrical and thermal characteristics of LEDs are measured by a T3Ster system, used for the electro-thermal modeling. It also identifies key variables (e.g., heat sink parameters) that can be designed to achieve a specified lifetime and reliability level. Two case studies of an indoor residential lighting and an outdoor street lighting application are presented to demonstrate the prediction procedures and the impact of different mission profiles on the lifetime of LEDs.