© 2019 Elsevier B.V. This systematic catalytic study reveals for the first time a strong size-activity relationship of iridium-based catalysts for the total oxidation of short chain alkanes reaction. Silica has been selected as support for its inertness and weak silica-iridium interaction to avoid its contribution to the catalytic activity. The size of the iridium particles can be increased from ∼5 to 27 nm by increasing the calcination temperature from 350 to 750 °C. Unlike other precious metals such as palladium or platinum, in the case of iridium catalysts, the oxidation activity increases when the size decreases. This effect is also maintained when the activity is normalized per metallic surface area revealing a higher intrinsic activity as the iridium size decreases beyond its simple increase in metallic surface area. Indeed, as the particle size decreases, a higher proportion of highly reducible iridium species as well as an increase in defective Ir 3+ species on the surface is observed by XPS, directly related to the enhanced activity. The highly reducible species are oxidized under the reaction conditions, leading to an initial decrease in activity before reaching a stable rate of oxidation reaction. This knowledge provides useful guidelines for the design of iridium-based systems for the total oxidation of volatile organic compounds at low temperatures.