The performance of the direct-contact membrane distillation (DCMD) process in desalting Mediterranean seawater was investigated. Theoretical and experimental optimization of various operating parameters was conducted. The effects of temperature differences, feed velocity, and membrane characteristics were studied. When using commercial polyvinylidene fluoride membranes, the vapor transfer throughout the membrane pores is dominated by the Knudsen-molecular diffusion model. Maximum permeate flux was obtained when increasing temperature, feed velocity, membrane pore size, and porosity and decreasing membrane tortuosity and thickness. Thermal efficiency, gained output ratio, and specific thermal energy consumption were improved when increasing feed temperature. By application of the DCMD process to Mediterranean seawater, a high water quality was obtained.