Mice of a Swiss substrain, reared under rigid pathogen-free (PF) conditions, were inoculated intranasally with broth cultures of Mycoplasma pulmonis ranging in dose from 10(1) to 9 x 10(9) colony forming units (CFU). A highly reproducible disease resulted with an LD(50) of 1.3 x 10(8) CFU and a PD(50) (dose producing pneumonia in 50% of mice) of 3.4 x 10(5) CFU. The inoculating dose of M pulmonis was found to be the critical determinant of the severity, duration and pathologic character of the respiratory disease produced. PF mice given 10(4) CFU or less developed a transient illness characterized by low frequencies of rhinitis, otitis media, laryngotracheitis and focal pneumonia. This was proposed as a low dose model. Doses of 10(5) to 10(9) CFU resulted in high frequencies of rhinitis, otitis media, laryngotracheitis and pneumonia. Within the first 10 days the pneumonia often was fatal, being characterized by an outpouring of neutrophils and edema fluid into alveolar spaces, pulmonary congestion and hemorrhage and, occasionally, pleuritis. This high dose-acute disease model was shown to be the result of seeding alveoli with large numbers of organisms at the time of intranasal inoculation. In animals surviving doses of 10(5) to 10(9) CFU beyond approximately 10 days postinoculation, the larger concentration of organisms was present in bronchi and bronchioles, giving rise to a third model, the high dose-chronic disease model. The predominant lesions were chronic suppurative bronchitis and bronchiolitis, marked peribronchial lymphoid cuffing, variable numbers of neutrophils and macrophages in alveoli, and complications such as bronchiectasis and pulmonary abscesses. Identical lesions were observed in axenic mice infected with M pulmonis. The infection in PF mice is considered a highly useful experimental system, both for comparative study of respiratory mycoplasmosis and for investigations directed toward understanding and eliminating the natural disease this agent causes in conventional mice and rats.