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Abstract: To maintain ultra-low particle concentrations, cleanrooms can require several hundred air changes per hour. These ventilation rates make cleanrooms 30–50 times more energy intensive than the average U.S. commercial building. There are an estimated 12millionm2 of cleanroom space in the U.S., consuming over 370PJ of energy each year. This paper explores opportunities to improve the energy efficiency of cleanrooms while maintaining or improving operating conditions. This paper documents the modeling of a 1600m2 cleanroom in upstate New York. The TRNSYS model includes TMY2 weather data; building geometry and material properties; empirical data on occupancy, lighting and process equipment; and sophisticated HVAC systems. The model was validated based on metered steam, chilled water and electricity usage. Under 8% error was achieved in all fields. Four strategies were simulated: a heat recovery system for exhaust air, resulting in an 11.4% energy reduction with a 2.7-year simple payback; solar preheating of desiccant dehumidifier regeneration air (2.4% energy reduction, 11.5-year payback); improved lighting controls (0.3% energy reduction, 1.5-year payback); and demand-controlled filtration (4.4% energy reduction, 3.1-year payback). Implementation of recommended strategies is predicted to save 9TJ, 862tonnes of CO2, and $164k annually. [Copyright &y& Elsevier]