Portable Emission Measurement Systems (PEMS) are used by the U.S. Environmental Protection Agency (EPA) to measure gaseous and particulate mass emissions from vehicles in normal, in-use, on-the-road operation to support many of its programs, including assessing mobile source emissions compliance, emissions factor assessment for in-use fleet modeling, and collection of in-use vehicle operational data to support vehicle simulation modeling programs. This paper discusses EPA’s use of Global Positioning System (GPS) measured altitude data and electronically logged vehicle speed data to provide real-world road grade data for use as an input into the Gamma Technologies GT-DRIVE+ vehicle model. The GPS measured altitudes and the CAN vehicle speed data were filtered and smoothed to calculate the road grades by using open-source Python code and associated packages. Ambient temperature, ambient pressure, humidity, wind direction, and speeds were used to simulate actual driving environment conditions, and to calculate vehicle performance, fuel economy, and emissions associated with environmental effects. Complete engine maps, transmission efficiencies, and vehicle data were used as inputs into the GT-DRIVE+ vehicle model to estimate fuel economy, greenhouse gas (GHG) and NOx emissions of a vehicle equipped with a 12-volt start-stop system. The model-simulated fuel economy, GHG and NOx emissions, engine torque, engine speed, and vehicle speeds were all in good agreement with the on-road measured fuel economy, GHG and NOx emissions from the PEMS vehicle test data.