Despite the growing popularity of new alternatives to traditional tobacco products, there is still limited evidence on their indoor effect in particular in residential spaces as specific environments where enforcement of air quality standards is difficult. Hence, the impact of the Tobacco Heating System 2.2 (THS, marketed as IQOS®) on indoor air quality was assessed under controlled experimental conditions using ventilation representative of residential buildings with natural ventilation. Smoking of cigarettes (Marlboro Gold®) at the same ventilation conditions and consumption rates was used as positive control. Before each THS 2.2 or Marlboro Gold session, a background session with the same volunteers as for the product-use session was held. In the high-load simulated residential environment, out of the 24 measured airborne constituents, only the increase of the indoor concentrations of nicotine, acetaldehyde, and glycerin above the background was attributable to the use of THS 2.2. The quantified concentrations of these three airborne compounds were significantly below the harmful levels defined in the air quality guidelines. Smoking Marlboro Gold resulted in much greater increases in the concentrations of all measured indoor air constituents, except for glycerin, and the indoor concentrations of several constituents exceeded the exposure levels set forth by cognizant authorities. Based on these data, it is reasonable to conclude that the use of THS 2.2 in environments where norms for indoor exposure in terms of adequate ventilation are respected does not adversely affect the overall indoor air quality.