Question: We sought to evaluate and compare the impact of lifetime exposure to cigarette smoke (CS) from the 3R4F reference cigarette with lifetime exposure to the aerosol from the Tobacco Heating System (THS) 2.2, a candidate modified risk tobacco product, on lung tumor incidence and multiplicity, the extent of lung inflammation and emphysematous changes, and systemic toxicity in the A/J mouse model. Methods: This study was performed in accordance with OECD Test Guideline 453 for combined chronic toxicity/carcinogenicity studies. Female and male A/J mice were whole-body exposed for 6 hours/day, 5 days/week for up to 18 months. Results: Exposure to CS for up to 5 months resulted in increased pulmonary inflammation, altered lung function, and emphysematous changes; CS exposure for up to 18 months increased lung tumor incidence and multiplicity. Such changes were not observed in THS 2.2 aerosol-exposed A/J mice. Histopathological changes in other respiratory tract organs were less severe in THS 2.2 groups compared to the CS group. Moreover, changes in red blood cell profiles, liver function parameters, and higher heart weight were noted in CS- but not THS 2.2 aerosol-exposed mice. However, lower organ weights for thymus and spleen, reduced blood lymphocyte counts, and reduced serum cholesterol and triglyceride concentrations were observed in both CS- and THS 2.2 aerosolexposed groups. Conclusions: THS 2.2 aerosol did not induce lung inflammation and emphysema, nor did it enhance lung tumorigenesis. Toxicological changes in THS 2.2 aerosol-exposed mice either showed no exposure-related changes, or effects, where observed, were either significantly reduced (upper respiratory tract organs) or comparable (spleen and thymus weights) to those observed in the CS-exposed mice.