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Electrostatic discharge (ESD) protection for mixed-voltage I/O interfaces has been one of the major challenges of system-on-a-chip (SOC) implementation in nanoscale CMOS processes. Moreover, the gate leakage current across thin gate-oxide devices has serious degradation on circuit performance while circuits implementing in nanoscale CMOS processes. The on-chip ESD protection circuit for mixed-voltage I/O buffers should meet the gate-oxide reliability constraints and be designed with consideration of gate leakage current. This paper presents the effective ESD protection scheme with circuit solutions to protect the mixed-voltage I/O buffers in nanoscale CMOS processes against ESD stresses. The proposed ESD protection scheme and the specific ESD clamp circuits with low standby leakage current have been successfully verified in nanoscale CMOS processes. Effective on-chip ESD protection scheme should be early planed and started in the beginning phase of chip design in order to achieve good enough ESD robustness for IC products.