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This paper discusses an efficient statistical analysis methodology for system-level signal integrity analysis. In the proposed method, statistical variations of the design and operational parameters are mapped to system performance through simulations based on orthogonal Taguchi arrays. Using the sensitivity functions derived from these simulations, statistical distributions of the performance measures are computed. The sensitivity functions and probability distributions of the design parameters are utilized as a diagnosis tool to estimate the design parameters of a system for a given measured performance. The statistical methodology is applied for design space exploration to improve system performance. For demonstrating the concept, a source synchronous memory bus and a peripheral input-output (I/O) bus have been analyzed under design and operational variations.