A calibrated building simulation model was developed to assess the energy performance of a large historic research building. The complexity of space functions and operational conditions with limited availability of energy meters makes it hard to understand the end-used energy consumption in detail and to identify appropriate retrofitting options for reducing energy consumption and greenhouse gas (GHG) emissions. An energy simulation model was developed to study the energy usage patterns not only at a building level, but also of the internal thermal zones, and system operations. The model was validated using site measurements of energy usage and a detailed audit of the internal load conditions, system operation, and space programs to minimize the discrepancy between the documented status and actual operational conditions. Based on the results of the calibrated model and end-used energy consumption, the study proposed potential energy conservation measures (ECMs) for the building envelope, HVAC system operational methods, and system replacement. It also evaluated each ECM from the perspective of both energy and utility cost saving potentials to help retrofitting plan decision making. The study shows that the energy consumption of the building was highly dominated by the thermal requirements of laboratory spaces. Among other ECMs the demand management option of overriding the setpoint temperature is the most cost effective measure.