The increasing prevalence of advanced chronic respiratory disease, with frequent exposure to broad-spectrum antibiotics for repeated and prolonged hospitalizations, favours the emergence of nosocomial respiratory infection by Gram-positive bacteria, such as outbreaks of Corynebacterium striatum. There is little evidence about patterns of respiratory infection, transmission and adaptive ability of this pathogen. Seventy-two C. striatum isolates from 51 advanced respiratory patients, mainly chronic obstructive pulmonary disease, were studied during 38 months. Patients were 74.8 ± 8.6 years old and 81.9% were men, who had required an average of 2.2 hospitalizations and 63.5 days in the hospital in the previous year. Of 49 isolates from 42 patients we were able to identify 12 clones by multilocus sequence analysis (MLSA), nine phenotypic variants and 22 antibiotic susceptibility patterns, and we determined their clinical and epidemiological determinants. MLSA allows identification of the existence of nosocomial outbreaks by transmission of the same or different clones, the persistence of the same clone in the environment or in patient airways for months. The study showed the high variability and adaptive capacity of the isolates, the antibiotic multidrug-resistance in all of them, and their contribution to a high morbidity and mortality (41%) during the study period.