Mixed convection heat transfer in a vertically oriented air-cooled square enclosure is simulated numerically using the finite volume method. The vertical left wall being heated and all others are considered insulated. The effects of six opposite and staggered inlet/outlet openings' locations over the top and bottom walls are investigated, with different sizes of the opening height (0.05 0.3). The objective is to figure out the better size and location of inlet and outlet to acquire more efficient cooling system in the enclosure by maximizing the heat removal rate. This is conducted over ranges of the governing parameters, which are the Richardson number (0 30) and the Reynolds number (50 250). The results show that the level of heat transfer enhancement increases with increasing the opening height, with an optimal size of d/H = 0.25 for obtaining maximum heat removal, for all Richardson and Reynolds numbers. The results also indicate that the higher heat dissipation occurs when the cold air is injected vertically near the hot wall and exits the enclosure from the opposite or staggered outlet, for all Richardson and Reynolds numbers.