The platinum-group metals (PGMs) are six neighboring elements in the periodic table of the elements. Each PGM can efficiently promote unique reactions, and therefore, alloying PGMs would create ideal catalysts for complex or multistep reactions that involve several reactants and intermediates. Thus, high-entropy-alloy (HEA) nanoparticles (NPs) of all six PGMs (denoted as PGM-HEA) having a great variety of adsorption sites on their surfaces could be ideal candidates to catalyze complex reactions. Here, we report for the first time PGM-HEA and demonstrate that PGM-HEA efficiently promotes the ethanol oxidation reaction (EOR) with complex 12-electron/12-proton transfer processes. PGM-HEA shows 2.5 (3.2), 6.1 (9.7), and 12.8 (3.4) times higher activity than the commercial Pd/C, Pd black and Pt/C catalysts in terms of intrinsic (mass) activity, respectively. Remarkably, it records more than 1.5 times higher mass activity than the most active catalyst to date. Our findings pave the way for promoting complex or multistep reactions that are seldom realized by mono- or bimetallic catalysts.