Mycoplasma ovipneumoniae (M. ovi) is a respiratory pathogen commonly found in sheep and goats. It is associated with mild to moderate respiratory disease in domestic lambs, but severe pneumonia outbreaks in wild ruminants, specifically bighorn sheep. The goal of our study was to better understand the role of M. ovi as a respiratory pathogen in domestic sheep and to explore potential antibiotic treatment approaches. We first established a flock of specific pathogen-free (SPF) lambs through supervised lambing and motherless rearing in a Large Animal BSL-2 facility. Lambs were fed a colostrum replacer that yielded low mortality, steady weight gain and serum IgG and protein concentrations comparable to those of lambs raised on ewe colostrum. We inoculated the SPF lambs with field isolates of M. ovi and monitored the lambs for eight weeks for colonization with the bacteria, M. ovi-specific antibodies, clinical symptoms, and cellular and molecular correlates of lung inflammation. After eight weeks, lambs were treated with the macrolide antibiotic gamithromycin and observed for an additional four weeks. Stable colonization of the upper respiratory tract with M. ovi was established in all four M. ovi-inoculated, but in none of the four mock-infected lambs. All M. ovi-infected lambs developed a robust antibody response to M. ovi within 2 weeks. However, we did not observe significant clinical symptoms, evidence of lung damage or inflammation in any of the infected lambs. Interestingly, treatment with gamithromycin failed to reduce M. ovi colonization. These observations indicate that, in the absence of co-factors, M. ovi causes asymptomatic colonization of the upper respiratory tract of that is resistant to clearance by the host immune response as well as by gamithromycin treatment in domestic lambs.