Photocatalytic oxidation (PCO) air cleaning is a promising technology suitable for the elimination of a broad range of volatile organic compounds (VOCs). However, performance of poorly designed PCO systems may be affected by the formation of volatile aldehydes and other partially oxidized byproducts. This study explored the role of key design and dimensioning parameters that influence the effective removal of primary pollutants and can help reduce or eliminate the formation of secondary byproducts. A model pollutant mixture containing benzene, toluene, o-xylene, undecane, 1-butanol, formaldehyde and acetaldehyde was introduced at a constant rate in a 20-m3 environmental chamber operating at an air exchange rate of 1 h−1. Individual pollutant concentrations were kept at realistically low levels, between 2 and 40 μg m−3. A prototype air cleaner provided with flat or pleated PCO filtering media was operated in an external ductwork loop that recirculated chamber air at flow rates in the range 178–878 m3 h−1, corresponding to recycle ratios between 8.5 and 38. Air samples were collected upstream and downstream of the air cleaner and analyzed off-line to determine single-pass removal efficiency. The final-to-initial chamber concentration ratio was used to determine the global chamber removal efficiency for each pollutant. In the flat filter configuration, longer dwelling times of compounds on the TiO2 surface were attained by reducing the recirculation airflow by a factor of ∼5, leading to increasing total pollutant removal efficiency from 5% to 44%. Net acetaldehyde and formaldehyde removal was achieved, the later at airflow rates below 300 m3 h−1, illustrating the critical importance of controlling the contact time of primary and secondary pollutants with the TiO2 surface. The use of pleated media was shown to increase significantly the system performance by extending the dwelling time of pollutants on the irradiated surface of the PCO media, with a 70% degradation of target pollutants. With the pleated media, formaldehyde removal efficiency increased to 60%. Irradiation using either a UVC or a UVA lamp under identical flow conditions produced similar pollutant elimination. A simple correlation between the steady-state single pass removal efficiency and the global chamber removal efficiency was used to rationalize these experimental results and identify optimal operating conditions.