Electrochemical measurements and in situ scanning tunneling microscopy (STM) are performed to establish a structure–reactivity correlation for peroxide or dioxygen reduction on underpotentially deposited (upd) Pb on Au(111) in 0.1 M HClO4. While STM imaging reveals the presence of Pb islands with height of 0.25±0.05 nm at the potential of highest catalytic activity toward the O2 and H2O2 reduction, the full Pb monolayer formed at −0.03 V vs. NHE shows about half the activity of the Pb islands. Ethanethiol (EtSH) significantly but not completely inhibits the H2O2 reduction activity of the Pb island structure. STM shows that EtSH introduction leads to the formation of a 0.13-nm-high terrace along the edges of the Pb islands, which is assigned to EtSH bound to the Au surface near the Pb islands with the alkyl chain oriented roughly perpendicular to the surface. These results show that edge sites around the Pb island are the active site of catalysis, though the sites atop the Pb islands may also take part in catalytic O2 reduction by Pb upd on Au(111).