The focus of this study is the evaluation of the effects of deficiencies in design-level values of effective binder content (ΔV<sub>be</sub>) on the top-down and bottom-up fatigue cracking performance of hot mix asphalt (HMA) mixtures using AASHTOWare Pavement ME Design structural simulation program. Using an analytical-mathematical-based methodology, this study also aims to predict the reduction in fatigue service life (i.e., top-down, and bottom-up fatigue cracking) of asphalt pavements that are most sensitive to the variation (ΔV<sub>be</sub>). Two types of mixes with varying levels of V<sub>be</sub> are used to simulate the fatigue cracking performance of a full-depth pavement structure. For each of the three studied cases, one asphalt course has a variable value of V<sub>be</sub>, while the two other courses have a fixed value of V<sub>be</sub>. Results indicate that the ΔV<sub>be</sub> of 3% reduced 50% to 70% of fatigue cracking service life. Additionally, Pavement ME shows a limitation to account for the effect of V<sub>be</sub> in the intermediate course on the bottom-up fatigue cracking.