The Food and Drug Administration (FDA) has recently classified the electronic cigarette (e-cig) with heat-not-burn technology IQOS as a modified risk tobacco product (MRTP), thus increasing the perception of its safety. To date, independent studies do not outline a clear toxicological profile of these devices and the World Health Organization (WHO) considers new electronic nicotine delivery systems (ENDSs) as potentially harmful. Furthermore, the “aerosol” generated by IQOS contains a large number of harmful substances such as tobacco specific nitrosamines (TSNA), toxic aldehydes, polycyclic aromatic hydrocarbons (PAH) and carbon monoxide, although in a lower concentration than conventional cigarettes (CCs). This study aimed to investigate the putative impact of IQOS aerosol on the liver, a secondary target, in an in vivo model. Male Sprague Dawley rats were exposed, whole body, for 4 weeks to IQOS aerosol and free radicals’ production, oxidative damage and antioxidant activity were analysed. Additionally, drug metabolism and mitochondrial enzymatic activity as well as lipidic profile were investigated. The results obtained indicates that IQOS devices may not only be harmful to primary target organs, such as the the lungs, but also affect liver function. The results, even if preliminary, support the precautionary attitude imposed by WHO towards these devices.