Mouse strains differ markedly in resistance to Mycoplasma pulmonis infection, and investigation of these differences holds much promise for understanding the mechanisms of antimycoplasmal host defenses. To determine the potential genetic diversity of resistance to disease in murine respiratory mycoplasmosis (MRM) and to select disease-resistant and nonresistant mouse strains for further genetic analysis, we screened 17 inbred mouse strains of various Bcg and H-2 genotypes for resistance to M. pulmonis. Mice were inoculated intranasally with 104 CFU of M. pulmonis UAB CT and evaluated at 21 days postinfection for severities of the four histologic lung lesions characteristic of MRM: alveolar exudate, airway exudate, airway epithelial hyperplasia, and lymphoid infiltrate. On the basis of these assessments of MRM severity, one group of mouse strains was found to be extremely resistant to disease (C57BR/cdJ, C57BL/6NCr, C57BL/10ScNCr, and C57BL/6J). The remaining strains of mice (C57L/J, SJL/NCr, BALB/cAnNCr, A/JCr, C3H/HeJ, SWR/J, AKR/NCr, CBA/NCr, C58/J, DBA/2NCr, C3H/HeNCr, C3HeB/FeJ, and C3H/HeJCr) developed disease of widely varying severities. Furthermore, strains in the group with more disease varied in pattern of lesion severity. While the severities of all four lesions were correlated in must mouse strains, this was not always true. DBA/2NCr mice had one of the highest scores for alveolar exudate, only a moderate score for airway exudate, and significantly lower scores for both airway epithelial hyperplasia and lymphoid infiltrate than all other strains susceptible to lung disease. DBA/2NCr mice had one of the highest mortality rates. We concluded that resistance to MRM is a complex trait. The observed differences in lung disease severity could not be explained by known differences at the Bcg or H-2 locus in the strains of mice we studied.