Tobacco use is associated with heart and respiratory diseases and also with a number of types of cancer. Tobacco smoke contains more than 6000 chemicals and among the most abundant ones are the aldehydes. Aldehydes have been previously shown in in vitro studies to induce intracellular oxidative stress and activation of stress signaling pathways, which are associated with cardiovascular diseases such as atherosclerosis. Also, aldehydes form one of the toxicant groups recommended for future tobacco product regulation due to its harmful effects. However, the in vitro effect of low-level aldehyde exposure has not been established. In this study, we determined the gene expression effects of aldehydes commonly found in tobacco smoke by exposing in vitro human umbilical vein epithelial cells (HUVECs) to these aldehydes. The most relevant aldehydes were used: formaldehyde, acetaldehyde, acrolein, propionaldehyde, crotonaldehyde and butyraldehyde. Sub-cytotoxic exposure levels of the different aldehydes were tested regarding cell proliferation, gene expression changes, oxidative stress responses, and DNA damage. Genes associated with cardiovascular disease development such as DEPP, ARID5B, DKK1, EGR1 and IER3 were found to be dysregulated. Gene expression responses were not related to the measurement of oxidative stress or DNA damage using a comet assay. These findings suggest that exposure to the low-level aldehydes from tobacco smoke needs to be controlled due to its effect on genes associated with cardiovascular disease.