Space heating is the largest energy end use, consuming more than 7 quintillion joules of site energy annually in the U.S. building sector. A few recent studies showed discrepancies in simulated space-heating energy use among different building energy modeling programs, and the simulated results are suspected to be underpredicting reality. While various uncertainties are associated with building simulations, especially when simulations are performed by different modelers using different simulation programs for buildings with different configurations, it is crucial to identify and evaluate key driving factors to space-heating energy use in order to support the design and operation of low-energy buildings. In this study, 10 design and operation parameters for space-heating systems of two prototypical office buildings in each of three U.S. heating climates are identified and evaluated, using building simulations with EnergyPlus, to determine the most influential parameters and their impacts on variations of space-heating energy use. The influence of annual weather change on space-heating energy is also investigated using 30-year actual weather data. The simulated space-heating energy use is further benchmarked against those from similar actual office buildings in two U.S. commercial-building databases to better understand the discrepancies between simulated and actual energy use. In summary, variations of both the simulated and actual space-heating energy use of office buildings in all three heating climates can be very large. However these variations are mostly driven by a few influential parameters related to building design and operation. The findings provide insights for building designers, owners, operators, and energy policy makers to make better decisions on energy-efficiency technologies to reduce space-heating energy use for both new and existing buildings.