Developing highly active and stable cathode catalysts is of pivotal importance for proton exchange membrane fuel cells (PEMFCs). While carbon-supported Pt-based catalysts have so far been the most active cathode catalysts, their durability and single-cell performance are yet to be improved. Herein, we report self-supported mesostructured Pt-based bimetallic (Meso-PtM; M = Ni, Fe, Co, Cu) nanospheres containing an intermetallic phase, combining the beneficial effects of transition metals (M), an intermetallic phase, a 3D interconnected framework, and a mesoporous structure. Meso-PtM nanospheres showed enhanced ORR activity, compared to Pt black and Pt/C catalysts. Notably, Meso-PtNi containing an intermetallic phase exhibited ultrahigh stability, showing enhanced ORR activity even after 50,000 potential cycles, whereas Pt black and Pt/C underwent dramatic degradation. Importantly, Meso-PtNi with an intermetallic phase also demonstrated superior activity and durability when used in a PEMFC single-cell, with record-high initial mass and specific activities.