The impact of the Tobacco Heating System 2.2 (THS 2.2) on indoor air quality was evaluated in an environmentally controlled room using ventilation conditions recommended for simulating “Office”, “Residential” and “Hospitality” environments and was compared with smoking a lit-end cigarette (Marlboro Gold) under identical experimental conditions. The concentrations of eighteen indoor air constituents (respirable suspended particles (RSP) < 2.5 μm in diameter), ultraviolet particulate matter (UVPM), fluorescent particulate matter (FPM), solanesol, 3-ethenylpyridine, nicotine, 1,3-butadiene, acrylonitrile, benzene, isoprene, toluene, acetaldehyde, acrolein, crotonaldehyde, formaldehyde, carbon monoxide, nitrogen oxide, and combined oxides of nitrogen) were measured. In simulations evaluating THS 2.2, the concentrations of most studied analytes did not exceed the background concentrations determined when non-smoking panelists were present in the environmentally controlled room under equivalent conditions. Only acetaldehyde and nicotine concentrations were increased above background concentrations in the “Office” (3.65 and 1.10 μg/m3), “Residential” (5.09 and 1.81 μg/m3) and “Hospitality” (1.40 and 0.66 μg/m3) simulations, respectively. Smoking Marlboro Gold resulted in greater increases in the concentrations of acetaldehyde (58.8, 83.8 and 33.1 μg/m3) and nicotine (34.7, 29.1 and 34.6 μg/m3) as well as all other measured indoor air constituents in the “Office”, “Residential” and “Hospitality” simulations, respectively.