In response to global climate change, there is a widespread push to reduce carbon emissions in the transportation sector. For the difficult to decarbonize heavy-duty (HD) vehicle sector, hybridization and lower carbon-intensity fuels can offer a low-cost, near-term solution for CO2 reduction. The use of natural gas can provide such an alternative for HD vehicles while the increasing availability of renewable natural gas affords the opportunity for much deeper reductions in net-CO2 emissions. With this in consideration, the US National Renewable Energy Laboratory launched the Natural Gas Vehicle Research and Development Project to stimulate advancements in technology and availability of natural gas vehicles. As part of this program, Southwest Research Institute developed a hybrid-electric medium-HD vehicle (class 6) to demonstrate a substantial CO2 reduction over the baseline diesel vehicle and ultra-low NOx emissions. The development included the conversion of a 5.2 L diesel engine to spark-ignited natural gas with an aluminum, pent-roof cylinder head to provide a diesel-like torque curve and engine NOx emissions below 0.02 g/hp-hr (0.027 g/kWh). In parallel, a vehicle modeling study was performed to determine an optimum hybrid architecture for an Isuzu F-Series truck to provide the largest impact on fleet emissions. Variations of motor/generator location, battery voltage, and storage capacity were evaluated. Finally, the demonstration truck was built with the prototype engine and P2 plug-in hybrid system to provide performance and emissions validation of the overall concept. The vehicle was tested over several HD drive cycles, including the Greenhouse Gas Emissions Model (GEM) certification cycles, and provided satisfactory performance. The GEM cycle results demonstrated a greater than 25% reduction in CO2 for the multi-purpose and urban subcategories. For the regional subcategory testing with a high percentage of highway speeds operation, the vehicle demonstrated a 13% reduction in CO2 due primarily to the lower carbon intensity fuel.