Objectives: Actinomycosis is a rare disease favored by disruption of the mucosal barrier. In order to investigate the impact of immunosuppression on outcome we analyzed the most severe cases observed in patients hospitalized in three tertiary care centers. Methods: We reviewed all cases of proven invasive actinomycosis occurring over a 12-year period (1997 to 2009) in three teaching hospitals in the Paris area. Results: Thirty-three patients (16 male) were identified as having an invasive actinomycosis requiring hospitalization. The diagnosis was made by microbiological identification in 26 patients, pathological examination in eight patients, and by both methods in one. Twenty patients (61%) were immunocompromised. Actinomycosis localization was abdominal or pelvic in 17 patients, thoracic in 11, cervicofacial in three, and neurological in two. Twenty patients (61%) underwent surgery. All strains were susceptible to amoxicillin. All patients were treated with a beta-lactam antibiotic, for a median length of 82 days. Twenty-eight patients (85%) were considered as cured. Overall mortality at hospital discharge was 21% (7/33). Mortality was higher in immunocompromised patients (7/20; 21%) compared to non-immunocompromised patients (0/13) (p = 0.027). However, six of seven deaths were directly related to the underlying disease. Conclusions: Actinomycosis is a cause of severe infection in immunocompromised patients and a surrogate marker of a poor prognosis in this specific population