Considering gate-oxide reliability, a new electrostatic discharge (ESD) protection scheme with an on-chip ESD bus (ESD_BUS) and a high-voltage-tolerant ESD clamp circuit for 1.2/2.5 V mixed-voltage I/O interfaces is proposed. The devices used in the high-voltage-tolerant ESD clamp circuit are all1.2 V low-voltage N- and P-type MOS devices that can be safely operated under the 2.5-V bias conditions without suffering from the gate-oxide reliability issue. The four-mode (positive-to-VSS, negative-to-VSS, positive-to-VDD, and negative-to-VDD) ESD stresses on the mixed-voltage I/O pad and pin-to-pin ESD stresses can be effectively discharged by the proposed ESD protection scheme. The experimental results verified in a 0.13-m CMOS process have confirmed that the proposed new ESD protection scheme has high human-body model (HBM) and machine-model (MM) ESD robustness with a fast turn-on speed. The proposed new ESD protection scheme, which is designed with only low-voltage devices, is an excellent and cost-efficient solution to protect mixed-voltage I/O interfaces.