BACKGROUND When the no observed adverse effect level (NOAEL) is determined by respiratory safety pharmacology, follow-up studies are warranted and may include airway resistance and compliance. Respiratory mechanics in commonly used large animal species (Beagle dogs, Cynomolgus monkeys, and Göttingen minipigs) were compared. METHODS Eighteen animals were used (3/sex/species) in an anesthetized model (propofol infusion) with pancuronium as a neuromuscular blocker. Parameters of respiratory mechanics were evaluated at baseline and at peak drug effect. Resistance (Rrs) and elastance (Ers) were measured by applying a single frequency forced oscillation (0.5 Hz) to the subject's airway opening and fitting the flow, volume and pressure data to the single compartment model of the lung. Increasing doses of intravenous (IV) methacholine were administered in all three species, as well as doubling aerosolized concentrations of the same bronchoconstrictor agent before and after inhaled albuterol. RESULTS The slope of the IV methacholine dose-response curve for Rrs was similar in dogs and monkeys and both species differed from minipigs, which showed greater reactivity. At the highest IV dose tested, minipigs also reached higher levels of bronchoconstriction than the other two species. They were followed, in decreasing order, by dogs and monkeys. Albuterol induced a significant decrease in the slope of the dose-response curve only in dogs and monkeys. CONCLUSIONS Scientific literature is available on respiratory mechanics in monkeys and dogs but not in minipigs. Our results suggest that minipigs were more reactive than dogs and monkeys to IV methacholine while less sensitive to inhaled albuterol.