A pavement mechanistic-empirical analysis is based on a pre-designed structure checked for required performance criteria. In case the latter are not met, this structure is modified and reprocessed. In this context, analyzing the effect of variations in project parameters on pavement performance prediction subsidizes a better understanding of results provided by computer programs. The objective of this study is to assess the effect of layer thickness and resilience modulus variations on flexible pavement performance. To do so, performance was estimated for the 20th project year through Elastic Layered System Model 5 (ELSYM5) software and American Association of State Highway and Transportation Officials (AASHTO) Mechanistic-Empirical method (ME). Using multiple regression models for result adjustment and through statistical assessments on regression coefficients calculated, it can be concluded that pavement lifespan consumption, predicted by simulations on ELSYM5, is sensitive to variations in coating and subbase thickness and in subgrade resilience modulus. For AASHTO ME method, predicted values for distresses were significantly sensitive to variations in coating, base and subbase thickness, and in base and subgrade resilience modulus. Comparing both approaches, it is concluded that ELSYM5 can be a viable alternative to the application of a ME pavement design method.