Heated tobacco product (HTP) aerosols have been shown to contain—on average—lower levels of known harmful or potentially harmful constituents (HPHCs) than smoke from conventional cigarettes. However, few studies have investigated the chemical composition of HTP aerosols beyond the routinely analyzed HPHCs (e.g., WHO-9, FDA-93). This study aimed to identify all constituents exclusive to or more abundant in an HTP aerosol produced by the Tobacco Heating System 2.2 (THS) than in smoke of a comparator cigarette (CC). To focus exclusively on chemical differences due to heating vs. burning tobacco, confounding factors were minimized by using the same tobacco in both test items without added flavorants. Untargeted analysis of whole aerosol and smoke samples using seven comprehensive liquid chromatography- and gas chromatography-mass spectrometry methods revealed that 92 % of analytical features were unique or significantly higher in CC smoke compared to 4.2 % in THS aerosol. A total of 31 distinct compounds were significantly more abundant in THS aerosol than CC smoke, and 29 of their chemical structures were assigned and confirmed using reference standards. A notable fraction of these compounds can be classified as glycerol reaction products. The only compound present exclusively in THS aerosol likely leached from a paper adhesive. These results support the hypothesis that heating tobacco to temperatures typical of HTPs does not produce compounds that are absent in CC smoke. Characterizing the compounds with intrinsically higher abundance in THS aerosol may provide valuable information to guide the chemical and toxicological evaluation of other types of HTP aerosols.