Cigarette smoking is a risk factor for chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). Apoe-deficient mice are prone to developing premature atherosclerosis and emphysema making it an ideal model in which both pathologies can be assessed simultaneously. We evaluated the effects of cigarette smoke (CS) from a conventional cigarette (3R4F) and from THS 2.2, a modified risk tobacco product (MRTP). Apoe-/- mice were exposed for up to 8 months to an aerosol from 3R4F or from (THS 2.2) 3hours/day, 5 days/week to a target nicotine concentration of 30 μg/l. After 2 months exposure to CS, cessation and switching groups were further exposed for up to 6 months to fresh air, or THS 2.2, respectively. A battery of markers of disease progression were investigated including atherosclerotic plaque formation, pulmonary inflammation (cell infiltration, cytokine levels), pulmonary function and lung emphysema. Exposure to CS induced time-dependent molecular, physiological and inflammatory responses in the lungs of Apoe-/- mice consistent with emphysematous changes. The size of atherosclerotic plaques measured in the aortic arches was higher in CS-exposed animals compared to both sham and pMRTP-exposed animals at all time-points examined. Micro computed tomographic (micro CT) analysis of aortic images after 8 months of exposure showed that larger plaque volumetric measurements in 3R4F-exposed animals than sham-exposed, cessation or MRTP-exposed mice. Significant changes in the lung transcriptome of Apoe-/- mice were observed in response to 3R4F-exposure compared to the gene expression levels observed in the transcriptome of sham-exposed mice. Smoking cessation and switching to THS2.2 resulted in lower activation levels compared to 3R4F. Both, smoking cessation and switching to the MRTP aerosol halted the rate of disease development as assessed by inflammatory, histopathological and molecular endpoints, typically within 1 to 3 months post exposure. Our work demonstrates the power of using the Apoe-/- mouse model to study comorbidities associated with cigarette smoking and investigate the mechanisms underlying the benefits of smoking cessation or switching to a MRTP.