Microporous, hydrophobic hollow fiber membranes were prepared from polyvinylidene fluoride (PVDF) under different processing conditions and by changing the composition of the polymeric dope. In particular, different additives were incorporated into the dope (Polyvinyl Pyrrolidone and Maleic Anhydride) and the molecular weight and the concentration of PVDF polymer into the dope solution (medium and high Mw, 15–18 wt.%) were varied, in order to obtain fibers with different morphologies. The prepared membranes were characterized in terms of morphology, mechanical properties, bubble point, overall porosity, pore size distribution and thickness. Comparison between their performance in membrane distillation (MD), working under vacuum and direct contact configurations was also performed. The trans-membrane flux obtained was related to the membrane properties, which are function of the operating spinning conditions and the polymeric dope composition. This systematic investigation is an attempt to establish a correlation between the MD performance (in terms of trans-membrane flux) and the hollow fiber preparation conditions (polymeric dope composition and spinning conditions).