Researchers at Argonne National Laboratory expanded the Greenhouse gases, Regulated Emissions, and Energy use in Transportation (GREET) model and incorporated the fuel economy and electricity use of alternative fuel/vehicle systems simulated by the Powertrain System Analysis Toolkit (PSAT) to conduct a well-to-wheels (WTW) analysis of energy use and greenhouse gas (GHG) emissions of plug-in hybrid electric vehicles (PHEVs). The WTW results were separately calculated for the blended charge-depleting (CD) and charge-sustaining (CS) modes of PHEV operation and then combined by using a weighting factor that represented the CD vehicle-miles-traveled (VMT) share. As indicated by PSAT simulations of the CD operation, grid electricity accounted for a share of the vehicle's total energy use, ranging from 6% for a PHEV 10 to 24% for a PHEV 40, based on CD VMT shares of 23% and 63%, respectively. In addition to the PHEV's fuel economy and type of on-board fuel, the marginal electricity generation mix used to charge the vehicle impacted the WTW results, especially GHG emissions. Three North American Electric Reliability Corporation regions (4, 6, and 13) were selected for this analysis, because they encompassed large metropolitan areas (Illinois, New York, and California, respectively) and provided a significant variation of marginal generation mixes. The WTW results were also reported for the U.S. generation mix and renewable electricity to examine cases of average and clean mixes, respectively. For an all-electric range (AER) between 10 mi and 40 mi, PHEVs that employed petroleum fuels (gasoline and diesel), a blend of 85% ethanol and 15% gasoline (E85), and hydrogen were shown to offer a 40-60%, 70-90%, and more than 90% reduction in petroleum energy use and a 30-60%, 40-80%, and 10-100% reduction in GHG emissions, respectively, relative to an internal combustion engine vehicle that used gasoline. The spread of WTW GHG emissions among the different fuel production technologies and grid generation mixes was wider than the spread of petroleum energy use, mainly due to the diverse fuel production technologies and feedstock sources for the fuels considered in this analysis. The PHEVs offered reductions in petroleum energy use as compared with regular hybrid electric vehicles (HEVs). More petroleum energy savings were realized as the AER increased, except when the marginal grid mix was dominated by oil-fired power generation. Similarly, more GHG emissions reductions were realized at higher AERs, except when the marginal grid generation mix was dominated by oil or coal. Electricity from renewable sources realized the largest reductions in petroleum energy use and GHG emissions for all PHEVs as the AER increased. The PHEVs that employ biomass-based fuels (e.g., biomass-E85 and -hydrogen) may not realize GHG emissions benefits over regular HEVs if the marginal generation mix is dominated by fossil sources. Uncertainties are associated with the adopted PHEV fuel consumption and marginal generation mix simulation results, which impact the WTW results and require further research. More disaggregate marginal generation data within control areas (where the actual dispatching occurs) and an improved dispatch modeling are needed to accurately assess the impact of PHEV electrification. The market penetration of the PHEVs, their total electric load, and their role as complements rather than replacements of regular HEVs are also uncertain. The effects of the number of daily charges, the time of charging, and the charging capacity have not been evaluated in this study. A more robust analysis of the VMT share of the CD operation is also needed.