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The purpose of this study was to evaluate and compare the cytotoxicity and gene expression profiles in cell cultures exposed to whole smoke generated from a full flavor cigarette (Test 1), a low tar cigarette (Test 2), and an ultra-low tar cigarette (Test 3). In addition, a reference cigarette 2R4F was evaluated for cytotoxicity. Neutral red (NR) cytotoxicity assay was performed to determine relative cell death at each exposure concentration (n = 6). LC50 was generated using wet total particular matter (WTPM), cigarette number, or nicotine concentrations. The overall order of cytotoxicity was Test 1 ≫ 2R4F ≈ Test 2 > Test 3. Cell culture samples were collected for RNA extraction at WTPM concentrations of each cigarette that gave similar nicotine concentrations. Affymetrix mouse whole genome 430 2.0 array was used to characterize the gene expression profiles for each cigarette. A total of 598 genes in Test 1, 176 genes in Test 2, and 234 genes in Test 3 samples were differentially expressed compared to the concurrent sham controls. The major biological processes associated with the changed genes in Test 1 samples were down-regulated DNA replication and cell proliferation; the same biological processes were much less affected in Test 2 and Test 3 samples. The common findings in all three cigarettes types were increased glutathione biosynthesis/consumption and inflammatory response, which are known biological effects caused by smoke exposure. The most significantly up-regulated genes were CYP1A1, GSTs, Hmox1, and Procr in smoke-exposed samples, which are either related to well-studied mechanisms of smoke exposure–related diseases or potential new biomarkers for assessing and monitoring biological effects of cigarette smoke exposure in vivo and in smokers. In summary, both the NR cytotoxicity assay and gene expression profiling were able to differentiate the three types of test cigarettes, and the results demonstrated reduced biological effects for the Test 2 and Test 3 cigarettes compared to the Test 1 cigarette in BALB/c-3T3 Cells. [ABSTRACT FROM AUTHOR]