Continuous changes in vehicle technology, road condition, traffic compositions initiate the change or updating of road users’ cost models. So that it needs to practice a continuous revision or update periodically for realistic estimation of costs and benefits. This paper presented the relationship and comparison between road users’ cost along Addis Ababa-Adama newly constructed expressway using the Highway Development and Management (HDM-4) Software and manually using formulations developed in the Portuguese model. The method started with data collection. All input data were collected from primary and secondary sources. The primary data utilized an interview, and secondary data were sourced out from pertinent documents, both published and unpublished. More data were gathered that related to vehicles. The vehicles using the road are classified based on the manual from the Ethiopian Road Authority as cars, utilities, small bus, large bus, small truck, medium truck, heavy truck, and truck trailer. The collected data have been input into the HDM-4 interface; the output of the analysis was vehicle operating costs, travel time, and road users’ cost as a summation. Using manual technique and HDM-4 Software, Birr 128.62/km/vehicle and Birr 139.23/km/vehicle, respectively, were found from road users’ costs analysis. The result shows the difference of Birr 10.61. Also, the correlation coefficient of 0.75 is determined, which shows that the two results of road users’ costs are highly related. As a result, the study reveals that the application of HDM-4 Software and the manual technique formulations from the Portuguese model can be adopted interchangeably to calculate Road Users’ Cost of road sections in Ethiopia. Hence, the study results are expected to be an eye-opener for a future similar project by the concerned agencies.