A new electrostatic discharge (ESD) protection design, by using the substrate-triggered stacked-nMOS device, is proposed to protect the mixed-voltage I/O circuits of CMOS ICs. The substrate-triggered technique is applied to lower the trigger voltage of the stacked-nMOS device to ensure effective ESD protection for the mixed-voltage I/O circuits. The proposed ESD protection circuit with the substrate-triggered technique is fully compatible to general CMOS process without causing the gate-oxide reliability problem. Without using the thick gate oxide, the new proposed design has been fabricated and verified for 2.5/3.3-V tolerant mixed-voltage I/O circuit in a 0.25-μm salicided CMOS process. The experimental results have confirmed that the human-body-model ESD level of the mixed-voltage I/O buffers can be successfully improved from the original 3.4 to 5.6 kV by using this new proposed ESD protection circuit.