This study develops a GIS-based framework model for estimating emissions from heavy-duty diesel vehicles (HDDV). We produce an emissions inventory for NOx, PM2.5, SO2, CO, and VOCs for a ten-state Midwest region (Mississippi Valley Freight Coalition) using roadway specific traffic data for 1999. Using MOBILE6.2 emission factors, a roadway level inventory is developed and used to evaluate emission sensitivity to transportation policy options. We compare our county and state estimates with the 1999 EPA National Emission Inventory (NEI). The EPA estimates are based on state totals of VMT disaggregated to the county level. We find that our NOx estimates for the region are 39% higher and our PM2.5 estimates are 17% lower than the EPA’s HDDV estimates. Most of the differences between emission inventories can be explained by differences in VMT estimates and vehicle speeds. The incorporation of detailed VMT and speed data explicit to the freight industry are fundamental to the production of an emission inventory that reflects the reality of HDDV activity in the region, and allows an evaluation of transportation impacts on regional air quality. Using this framework, we evaluate two policy scenarios: the 2007 Heavy-Duty Highway Rule and a potential regional reduction in posted speed limits. We find that the 2007 Heavy-Duty Highway Rule will result in HDDV NOx and PM2.5 emissions in 2010 to be 54% and 67% less than 1999 emissions. These reductions are expected even as HDDV VMT in the region will increase 40% over the same time period. Furthermore, by reducing posted speed limits; lowering average 39 HDDV speeds on highways by 10 mph, NO can be reduced by 26%.