Mycobacterium simiae is a rare species of slow-growing nontuberculous mycobacteria (NTM). From 2002 to 2017, we conducted a retrospective study that included all patients with NTM-positive respiratory samples detected in two university hospitals of the French overseas department of Reunion Island. We recorded the prevalence of M. simiae in this cohort, as well as the clinical, radiological, and microbiological features of patients with at least 1 sample positive for M. simiae. In our cohort, 97 patients (15.1%) were positive for M. simiae. Twenty-one patients (21.6%) met the American Thoracic Society (ATS) criteria for infection. M. simiae infection was associated with bronchiectasis, micronodular lesions, and weight loss. Antibiotic susceptibility testing was performed for 60 patients, and the isolates were found to have low susceptibility to antibiotics, except for amikacin, fluoroquinolones, and clarithromycin. Treatment failed for 4 of the 8 patients treated for M. simiae infection. Here, we describe a specific cluster corresponding to a large cohort of patients with M. simiae, a rare nontuberculous mycobacterium associated with low pathogenicity and poor susceptibility to antibiotics.