Rhodococcus equi infection is rare in humans, but has increasingly been reported in the last three decades, particularly in immunocompromised patients. The infection is mainly pulmonary but can also assume an extra-pulmonary form. R. equi infection is difficult to diagnose at an early stage both from a clinical and microbiologic view. Only correct and timely diagnosis and treatment can help reduce significant morbidity and mortality. Optimal treatment probably consists of prolonged, preferably triple combination therapy, including vancomycin, with optimization of pharmacokinetic parameters and screening for drug interactions, when indicated. Two clinical cases of invasive R. equi infection are reported in this manuscript: a pulmonary form and an extra-pulmonary form with brain abscesses, both in immunocompromised patients, with detailed description of symptoms, analysis, treatment, and outcome.