Due to several apparent advantages over methanol, dimethyl ether (DME) has been viewed as a promising alternative fuel for direct fuel cell technology. Similar to methanol, DME oxidation requires a surface oxidant, such as OH, for the removal of adsorbed CO. Consequently, the reaction occurs at much faster rates on binary PtRu catalysts than Pt alone. In this work, PtRu catalysts with a wide variety of Pt-to-Ru ratios were systematically studied in the direct DME fuel cell (DDMEFC) operating at 80 °C. A Pt50Ru50 catalyst was found to perform the best at high and middle voltages, while a Pt80Ru20 catalyst performed best at low voltages. DDMEFC operation conditions, such as DME flow rate, anode back pressure, DME-to-water molar ratio, and membrane thickness, were also studied in order to maximize the cell performance. A maximum power density of 0.12 W cm−2 obtained in this work exceeds the highest reported DME performance. In comparison with the direct methanol fuel cell (DMFC), the optimized DDMEFC performs better at cell voltages higher than 0.55 and 0.49 V with feed concentrations of methanol of 0.5 and 1.0 M, respectively.