A combination of ventilation and air cleaning regimes were investigated for the removal of aerosol particles and volatile organic compounds (VOCs) in a test chamber, representing a typical room. A series of portable multi-staged air cleaner efficiency tests were performed examining tobacco smoke as a source of pollution. Portable indoor air cleaners were effective in removing of particles, reaching up to 97% removal efficiency based on particle number concentrations after 30 minutes, while Clean Air Delivery Rate (CADRPNC) varied from 37 ± 4 to 237 ± 11 m3 h–1. The removal of VOCs varied from 21.4 to 45.7% and CADRVOC ranged from 2.2 ± 0.3 to 29.9 ± 2.8 m3 h–1, indicating substantially lower efficiency. The combination of ventilation and air cleaning provided different responses with respect to pollutant removal and energy efficiency. The air cleaning was the most efficient for removing particulate matter from indoor air, minimizing the requirement for ventilation. On the other hand, the ventilation seemed to be more efficient in the removal of VOCs, while the combination of ventilation and air cleaning increased pollutant removal efficiency by 20% and maximized the energy efficiency.