The economic growth in developing countries triggers investments in highway networks. Thus, this requires a re-evaluation of existing design practices, which are mostly empirical. An alternative is the relatively recently developed Mechanistic-Empirical (M-E) design method. It has major data challenges and must be identified before a major switch. In this study, three different climatic regions for Turkey were analyzed optimizing 162 design combinations. Results showed that climate, traffic, and reliability parameters extremely affect the performance of the pavement. As in the current practice of Turkey, climate and material effects are not currently considered; these should be further studied considering the local calibration steps.