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This paper discusses an efficient method to analyze the spatial and temporal reliability of analog and digital circuits. First, a SPICE-based reliability simulator with automatic step-size control is proposed. Both hot carrier degradation and negative bias temperature instability are included in the simulator. Next, a method to analyze the interaction between process variability effects and circuit aging is introduced. This method is based on a screening experimental design (DoE) succeeded by a set of regression DoEs, resulting in a good speed-accuracy tradeoff with a nearly linear complexity for all circuits under test. Finally, based on the DoE analysis, a circuit response surface model (RSM) is derived. The RSM is used for further circuit reliability analysis such as circuit weak spot detection and yield calculation as a function of circuit lifetime. The proposed method is validated over a broad range of both analog and digital circuits. Yield simulation time is reduced with up to three orders of magnitude, when compared to standard Monte Carlo-based techniques and while still maintaining simulation accuracy.