Museums are dedicated to protect their artwork collection and to display the collection as safely as possible. Amongst other things, the indoor climate is of utmost importance to minimize collection degradation. Many museums employ tight climate guidelines, allowing only small fluctuations of indoor temperature and relative humidity, resulting in the following problems: huge energy consumption, the need for high-capacity HVAC systems, additional stress on historical buildings. This simulation study investigates the energy-saving potential of different setpoint strategies. Damage functions were used to assess the degradation risk of the collection and an Adaptive Temperature Guideline was used to assess thermal comfort. A state-of-the-art museum in the Netherlands was modeled and the indoor climate and energy consumption were simulated, including heating, cooling, humidification and dehumidification. Maximum savings, compared to a reference situation, of 82% may be achieved. However, the optimum strategy yields a saving of 77%, significantly improves thermal comfort and decreases chemical degradation.