Heat removal efficiency (HRE) is a widely used ventilation performance index regarding energy efficiency. This chapter develops an empirical model of HRE and demonstrates its convenient and effective applications in energy-efficient air-side modulation approaches. The proposed HRE model is constructed as a mathematical function integrating supply air temperature, supply airflow rate, and cooling load as key variables. Extensive validation across thirty-three experimental scenarios and five simulated cases demonstrates its applicability to both stratum and displacement ventilation systems in diverse room geometries and air terminal configurations. The model’s prediction errors remain within 5% for most cases, with a mean absolute error below 4%, underscoring its reliability. Investigations into air-side modulation using this HRE model reveal that variable-air-volume systems can effectively manage a broader spectrum of cooling loads compared to constant-air-volume systems in typical stratum-ventilated classroom and office environments. The conventional assumption of a constant HRE value in traditional methods can lead to significant room temperature prediction errors, reaching up to ±1.3 °C, which highlights the critical role of the proposed model in ensuring occupant thermal comfort during air-side control. An optimized air-side modulation strategy based on maximizing HRE is introduced, aiming to enhance energy efficiency while maintaining acceptable thermal conditions. Results indicate that this approach can improve the energy efficiency of stratum ventilation systems by up to 67.3%, with promising implications for displacement ventilation applications as well.