Animal models for cigarette smoke associated diseases are important for research studies of the mechanisms involved in disease pathogenesis. We have developed an exposure protocol that results in cardiovascular dysfunction in the exposed mice. Male C57BL/6 mice, 8-9 weeks of age, were exposed to whole body mainstream and sidestream cigarette smoke generated from 3R4F reference research cigarettes that deliver 9.4mg tar and 0.726mg nicotine per cigarette under the standard Cambridge filter smoking condition. The smoking machine was programmed to puff smoke over a period of ~24 min (240 puffs), followed by a break of fresh air for ~20 min. The total exposure time was ~72 min per day 6 days per week for 8, 16, 32 or 48 weeks. Exposure concentrations and durations, concentrations of NO, NO₂, O₂, HCN, H₂S, NH₃, SO₂, CO, and volatile organic compounds were closely monitored to assure reproducibility of daily exposure. We observed significant changes in the arterial blood pressure and vascular endothelial function as manifestations of smoke-induced cardiovascular disease. Blood carboxyhemoglobin kinetics were also measured. Since cigarette smoke contains several gases including NO, CO, and H₂S that are known signaling molecules and can protect against or modify disease, it is important to measure their concentrations and correlate these with the induction and severity of disease.