Chronic exposure to cigarette smoke (CS) is a risk factor for the development and progression of cardiovascular disease. Considerable attention has been given to the potential reduced harm of e-vapor products. ApoE-/- mice were used to evaluate atherosclerosis development, cardiac function, and aortic stiffness upon exposure to fresh air (Sham), CS from a 3R4F reference cigarette, or e-vapor aerosols generated using capillary aerosol generators from various e-vapors (“CARRIER” containing humectants [propylene glycol, glycerin], “BASE” containing humectants and nicotine, and “TEST” containing humectants, nicotine, and flavors). ApoE-/- mice were exposed for three hours per day for six months via whole-body inhalation. Measurement of lipoprotein cholesterol concentration, quantification of atherosclerotic plaque formed, and ultrasound scans of the hearts and aortas were performed. Total serum and very low-density lipoprotein cholesterol were increased in the 3R4F group at Months 3 and 6 but were reduced in the BASE and TEST groups compared with the Sham or CARRIER groups at Month 6. In contrast to CS, exposure to any of e-vapor groups did not increase aortic plaque formation when compared with the Sham group. CS exposure was associated with an impairment of both systolic and diastolic cardiac function, as assessed by ejection fraction, fractional shortening, isovolumic relaxation time, and E/A ratio. A subtle impairment of systo-diastolic performance, as assessed by myocardial performance index, was observed in BASE and TEST groups when compared with the Sham or CARRIER groups. All groups containing nicotine (CS, BASE, and TEST) displayed increased stiffness of abdominal aorta and carotid artery, with the effect being most prominent in the CS group. In conclusion, chronic CS exposure aggravated atherosclerosis, which was not observed in the e-vapor aerosol-exposed groups. Increased aortic stiffness was more pronounced in the CS-exposed group as compared with nicotine-containing e-vapor aerosol-exposed groups.