Models of emphysema produced by exposing animals to cigarette smoke (CS) have potential for use in testing treatments of this disease. To better characterize development of emphysema in an animal model, male and female mice of the B6C3F1 and A/J strains were exposed to CS at 250 mg total particulate material (TPM)/m3 for 15 weeks. Emphysema was evident in both strains of mice to differing degrees of severity. The CS-induced increase in the mean linear intercept (normalized to BW) of A/J mice was 51% greater than the control value, while CS-exposed B6C3F1 had an increase of 38% in this morphometric measurement of alveolar air space enlargement. In separate experiments, female B6C3F1 mice and male A/J mice were exposed to CS for 32 weeks and 15 weeks, respectively, and were then used to test the efficacy of all trans-retinoic acid (ATRA) treatments to ameliorate emphysema lesions. Following CS exposure, the B6C3F1 mice were treated once daily for 14 days in a 3-week period by nose-only inhalation exposure to aerosols of 180 or 1,800 mg-minutes ATRA/m3. The A/J mice were treated once daily, 4 days/week, for three weeks by either intraperitoneal injection of ATRA (0.5 or 2.5 mg/kg) or inhalation exposure to ATRA (3,600 or 18,000 mg-minutes/m3). Neither the injections nor inhalation exposures of ATRA in either strain of mouse caused reversal of the emphysema. In summary, CS-induced emphysema was more severe in A/J mice than in B6C3F1 mice. Treatment with ATRA did not reverse emphysema in either strain of CS-exposed mice.