Microfluidic fuel cell (MFC) is a new type of fuel cell which utilizes two laminar flows as electrolyte for both reactant delivery and ionic conduction purposes. According to the flow configuration, two MFC designs, that is, the co-flow cell and the counter-flow cell, have been proposed in the literature, but the specific merits and demerits between them have not been well understood yet. Therefore, in this work both experimental and numerical comparative studies are conducted on this issue. It is found that the counter-flow MFC encounters an inherent drawback on its power output because the outer part of its electrodes contributes much less than the inner part due to the longer ionic transport path. In conclusion, short and wide electrodes are more appropriate for counter-flow MFCs rather than the conventional long and narrow ones. Nevertheless, the counter-flow MFC does exhibit great advantage on low flow rate tolerance, leading to much improved fuel utilization and energy density at the same time. Considering this huge superiority for real applications, structural optimization of the counter-flow MFC is further conducted by reducing the electrode distance and discarding the outer part of the electrodes. The optimized counter-flow cell performance is successfully improved to the same level with its co-flow counterpart.