Thirdhand smoke (THS) is the persistent residue of tobacco and/or tobacco smoke that has sorbed onto surfaces, including household dust. Past studies examined environmental tobacco smoke in indoor environments using compounds such as nicotine as a marker for the presence of THS. In this study, our objective was to identify other compounds indicating tobacco and/or tobacco smoke in household dust. Household dust samples from ten homes of smokers and nine homes of non-smokers were analyzed by a nontargeted analytical approach using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC/TOF-MS). A total of 140 compounds were selected, having an average chromatographic peak abundance at least five times greater in smokers’ homes than non-smokers’ homes. From these 140 compounds, forty-two compounds were selected as highly identifiable compounds with the highest mass spectral similarity based on their high mass spectral matching with the NIST mass spectral library. This study found that from these forty-two highly identifiable compounds, fourteen were found to be significantly higher in smokers’ homes than non-smokers’ homes. These fourteen compounds were: 1,3,5- cycloheptatriene; 2,3'-dipyridyl; p-isopropoxyaniline; propanoic acid 2-methyl-, 1-(1,1- dimethylethyl)-2-methyl-1,3-propanediyl ester; myosmine; nicotine; nicotyrine; nornicotyrine; 2-propenoic acid, 3-phenyl-, methyl ester; pyridine, 3-ethenyl; 4(1H)- pyridone; 2,3-Quinoxalinedione, 1,4-dihydro-6-methyl-; scopoletin; tri(2-chloroethyl) phosphate. This study also found eight compounds which could potentially be present in THS in household dust: 1,2-benzenediol,3-(1H-1,2,3,4-tetrazol-5-yl)-; bicyclo [2.2.1] heptane-2- carboxylic acid,3,3 dimethyl-; cholest-5-en-3-ol (3á)-, tetradecanoate; cyclooctane, 1,2- diethyl-; tau-muurolol; 3-oxabicyclo [3.3.0] octan-2-one,7-neopentylidene-; pentan-2-ol, 4- allyloxy-2-methyl-; and phthalic acid, isobutyl 7-methyloct-3-yn-5-yl ester. These findings suggest that the fourteen statistically significant compounds can serve as markers of THS which may help to understand behaviors and fate of THS in indoor environments and assess exposure assessment.