Cor pulmonale is a significant cause of morbidity and mortality in patients with emphysema but it is not known whether alveolar destruction is directly involved in the disease pathogenesis. The purpose of this study was to examine the relationship between susceptibility to smoking-induced cor pulmonale and alveolar destruction in 8 inbred strains of mice: 129XI/SvJ, A/J, A/HeJ, BALB/cJ, C3H/HeJ, C57BL/6J, DBA/2J, and SWR/J. The mice were exposed to filtered air or mainstream cigarette smoke at a concentration of 250 mg/m³ for 5.5 hours/day, 5 days/week for 5 months, housed for 4 more months, and sacrificed. The ratio of the weight of the right ventricle / left ventricle plus septum RV/(LV+S) was used to assess right ventricular hypertrophy. Alveolar mean linear intercept was used to quantify severity of alveolar destruction. Morphometric determination of blood vessel muscularization was done on sections from 4 mouse strains. Smoke exposure resulted in significant increases in RV/(LV+S) in the A/J and AHE strains compared to air-exposed controls. The magnitude of the smoking-induced increase in RV/(LV+S) decreased as a function of the genetic distance of the other strains from the A/J and A/HE strains. Pulmonary vascular muscularization was significantly increased in smoke-exposed A/J and BALBc mice but not in C3H/HeJ and C57BL/6 mice. Also, mouse strain susceptibility to smoking-induced pulmonary vascular muscularization did not correlate with changes in mean linear intercept. The data from this study suggest that alveolar destruction by itself is not sufficient to cause smoking-induced cor pulmonale in inbred mice.