Syrian Golden hamsters develop severe emphysema after a single intratracheal dose of elastase whereas Sprague Dawley rats exhibit mild emphysema with the same dose/kg of body weight. We hypothesized that the development of severe emphysema is prevented in rats by the high serum level of alpha1-antitrypsin reported in rats in comparison to hamsters, that provides for a high lung elastase inhibitory capacity (EIC). To explore this possibility we challenged the antiprotease system of the rats by treating them with three similar weekly doses of elastase. Four months after treatment we evaluated changes in histology, volume and elastic properties of rat lungs and compared them with those of hamsters receiving a single dose of elastase. We also measured serum alpha1-antitrypsin levels and serum and lung EIC in control rats and hamsters. Results showed that, in association with a 40% less serum and lung EIC when compared to rats (p<0.001), hamster lungs had upper lobe-bullae formation, severe microscopic emphysema, a four-fold increase in lung volume (p<0.01) and a three-fold increase in constant k, an index of compliance, of the lung deflation pressure-volume curve (p<0.01). In contrast, rats developed mild emphysema, with only 50% increase in volume (p<0.05) and 60% increase in constant k (p<0.01). In conclusion, two species that differ in serum and lung EIC, exhibit significant differences in emphysema development after elastase. Rats with high EIC, despite receiving three doses of elastase, showed significantly less derangement of morphological and physiological parameters than hamsters with low EIC receiving a single dose.