Proton exchange membrane water electrolysis (PEMWE) is a promising technology to produce hydrogen directly from renewable electricity sources due to its high power density and potential for dynamic operation. Widespread application of PEMWE is, however, currently limited due to high cost and low efficiency, for which high loading of expensive iridium catalyst and high OER overpotential, respectively, are important reasons. In this study, we synthesize highly dispersed IrRu nanoparticles (NPs) supported on antimony-doped tin oxide (ATO) to maximize catalyst utilization. Furthermore, we study the effect of adding various amounts of Ni to the synthesis, both in terms of catalyst structure and OER activity. Through characterization using various X-ray techniques, we determine that the presence of Ni during synthesis yields significant changes in the structure of the IrRu NPs. With no Ni present, metallic IrRu NPs were synthesized with Ir-like structure, while the presence of Ni leads to the formation of IrRu oxide particles with rutile/hollandite structure. There are also clear indications that the presence of Ni yields smaller particles, which can result in better catalyst dispersion. The effect of these differences on OER activity was also studied through rotating disc electrode measurements. The IrRu-supported catalyst synthesized with Ni exhibited OER activity of up to 360 mA mg_PGM^–1 at 1.5 V vs RHE. This is ∼7 times higher OER activity than the best-performing IrO_x benchmark reported in the literature and more than twice the activity of IrRu-supported catalyst synthesized without Ni. Finally, density functional theory (DFT) calculations were performed to further elucidate the origin of the observed activity enhancement, showing no improvement in intrinsic OER activity for hollandite Ir and Ru compared to the rutile structures. We, therefore, hypothesize that the increased activity measured for the IrRu supported catalyst synthesized with Ni present is instead due to increased electrochemical surface area.