Rhodococcus equi is an opportunistic intracellular pathogen that causes pyogranulomatous pneumonia in foals and immunocompromised people, and is clinically and microbiologically similar to tuberculosis (TB). Currently, no model exists of R. equi pneumonia other than intra-bronchial infection of foals with R. equi. Because infection of foals is labor-intensive and costly, a guinea pig (GP) model of R. equi pneumonia would be of great benefit for evaluating novel approaches for control and prevention of this disease (and possibly TB). Our objective in this study was to develop a GP model of R. equi pneumonia. Groups of 6 GPs were infected with either 101, 102, 103, or 104 CFU of virulent R. equi strain using a Madison aerosol chamber, and groups of 6 GPs were infected with either 106, 107, or 108 CFU of virulent R. equi intratracheally. GPs were observed daily for clinical signs of pneumonia, and were euthanized on days 1, 3, 7, 14, or 35 post-infection (PI). Necropsy was performed and lungs were weighed, homogenized with PBS, and plated onto selective agar to determine bacterial load. No clinical signs of the disease or gross pathologic changes were observed regardless of the inoculum or mode of infection; histopathological findings of lungs are pending. Viable bacteria recovered from the lungs increased on day 3 PI, but decreased on day 7. No bacteria were recovered from animals euthanized either 2 or 5 weeks PI. Despite being highly susceptible to the agent of TB, GPs appear to be resistant to pulmonary infection with virulent R. equi at high doses. These remarkable findings suggest that this model might reveal novel mechanisms of resistance to natural infection with R. equi, which could inform the development of prophylactic or therapeutic approaches.