Hepatic lipid metabolism is profoundly affected by cigarette smoke; which likely contributes to the atherogenic plasma lipid profile observed in cigarette smokers. There is, however, a paucity of data on the identification of molecular networks and mechanisms responsible for the reduction of cardiovascular risk in former smokers compared to the risk of current smokers. Using ApoE-/- mice, an experimental model exhibiting a high atherogenic rate that leads to rapid development of vascular lesions, we investigated the effects of discontinuing smoke exposure on both hepatic lipid and transcriptome profiles. Livers from ApoE-/- mice exposed to: (i) mainstream smoke of the reference research cigarette 3R4F for six months (CS), (ii) fresh air for six months (sham exposed), or (iii) CS for three months followed by fresh air for three months (cessation), were extracted and their lipid composition analyzed on six different mass spectrometry platforms. Targeted and non-targeted mass spectrometry methods allowed quantification of more than 200 lipid species. The liver transcriptomes of the same animals were profiled using Affymetrix arrays. With the exception of Triacylglycerols (TAGs), most lipid species that were elevated in liver as a result of cigarette smoke exposure were decreased during the smoking cessation protocol. They included free and esterified cholesterol, phospholipids, sphingomyelins, and ceramides. The hepatic concentration of TAGs was higher in the cessation group as compared to the sham or CS groups. Gene Set Enrichment Analysis (GSEA) of the transcriptomes of the three experimental conditions revealed key hepatic functions affected by CS exposure and smoking cessation, including glutathione metabolism, oxidoreduction, and lipid biosynthesis. A subset of mice across the three experimental groups displayed up regulation of a set of genes consistent with an exocrine pancreas signature. Investigating the simultaneous changes on the hepatic lipidome and transcriptome in a murine model of atherosclerosis enabled the characterization of a liver-specific profile in response to smoking cessation. This information supports our efforts to develop an integrative model of key metabolic changes induced by cigarettes smoke and smoking cessation in tissues relevant to atherogenesis, including blood vessels, adipose tissue and liver.