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Three system-level electrostatic discharge (ESD) design methodologies are compared using an RF buffer amplifier as case study. First, the system-level ESD protection is designed with datasheet information. The obtained overdesigned ESD protection is optimized with the System-Efficient ESD Design (SEED) methodology. The SEED-based protection design is further optimized using human metal model testing and transient simulations. The final ESD protection design requires five times less area on the application board, and the capacitive loading is six times lower than when designing with datasheet information.