A patient with human immunodeficiency virus infection developed anterior mediastinitis during antibiotic treatment for empyema due to Rhodococcus equi. This is the first reported case of infection with this organism in this setting. Despite an adequate course of therapy and maintenance treatment with antibiotics to which the isolate of Rhodococcus equi was susceptible in vitro, the patient experienced relapse of the infection into the mediastinum. Clinicians should consider this complication when Rhodococcus equi is present in pleural effusions.