Commercial vehicle fuel economy is known to vary significantly with both positive and negative road grade. Medium- and heavy-duty vehicles operating at highway speeds require incrementally larger amounts of energy to pull heavy payloads up inclines as road grade increases. Non-hybrid vehicles are unable to recapture energy on descent and lose energy through friction braking. While the on-road effects of road grade are well understood, the majority of standard commercial vehicle drive cycles feature no road grade requirements. Additionally, the existing literature offers a limited number of sources that attempt to estimate the on-road energy implications of road grade in the medium- and heavy-duty space.This study uses real-world commercial vehicle drive cycles from the National Renewable Energy Laboratory's Fleet DNA database to simulate the effects of road grade on fuel economy across a range of vocations, operating conditions, and locations. Road grade data is appended to real-world drive cycles using the United States Geological Survey's 1/3 arc-second digital elevation model. Real-world drive cycles are then paired with vocation-specific vehicle models and simulated with and without grade. Percentage fuel use increase due to grade is presented, and variation in fuel consumption due to drive cycle and vehicle characteristics is explored through graphical and statistical comparison. The results of this study suggest that road grade accounts for 1%-9% of fuel use in commercial vehicles on average and up to 40% on select real-world drive cycles.