Portable air cleaners have demonstrated their effectiveness in reducing indoor PM concentrations. Common rating systems assume the air cleaner is in a room having limited air exchange with ambient air and the rest of the building. In this analysis, we model conditions in which people operate air cleaners in rooms with some natural ventilation. METHODS: A simplified mass balance model was developed for a 50 m3 room within a 350 m3 home, assuming well-mixed spaces, homogeneous infiltration, and applying the LBLX ventilation model. Natural ventilation was through a hung window in the room, open between 0 and 80 cm. The air cleaner was sized to minimum CADR rating. Ambient PM concentrations, temperature and wind speed, and the strength and location of indoor sources were varied. Effectiveness was defined as the reduction in indoor PM concentration compared to the same scenarios with the air cleaner off. RESULTS: The relative effectiveness depended only on the air exchange rate of the room, regardless of source strength and location, and ranged from almost 80% (the filtration efficiency) under recommended conditions (<1 ach), to less than 20% with maximum window opening (14 ach), under mild weather conditions (5 ̊C temperature difference, 2.5 m/s wind speed). Opening the window while operating the air cleaner was a more effective strategy to reduce indoor PM concentrations when the dominant PM source was located inside the room and ambient air concentrations were moderate. The reverse approach applied when ambient PM dominated. CONCLUSIONS: Air cleaners can still reduce indoor pollutants when used in conjunction with natural ventilation under a wide range of conditions. This work may help inform user guidelines for air cleaners.