The impact of ventilation strategies on the energy performance of new and existing buildings located in the Mediterranean is the main objective of the study. Several design criteria have been implemented in a base case reference model of a residential building, in order to achieve the net zero-energy balance target. The basic ventilation scenario adopted in the study as a reference, involved the moderate application of natural ventilation in summer months. Various modifications of this ventilation strategy that include the gradual scaling-up of the ventilation rate and the application of mechanical ventilation have been simulated, and their effect on primary energy demand required photovoltaic (PV) capacity and indoor thermal conditions evaluated. The results of the analysis indicate that the application of mechanical ventilation resulted in considerable increase of energy demand, up to 20%. Although the implementation of mechanical ventilation provides better control of indoor temperature distribution, the induced increase of energy consumption along with the installation and maintenance costs render such a solution less suitable for residential buildings in the Eastern Mediterranean, compared to natural ventilation.