BACKGROUND Vibrio vulnificus can cause a rapidly progressive fatal soft-tissue infection. Staphylococcus aureus is the most common cause of skin and soft-tissue infections reported worldwide, and, in particular, methicillin-resistant Staphylococcus aureus has emerged as the most common isolate in emergency departments. The purposes of the present study were to compare the specific characteristics of Vibrio vulnificus and Staphylococcus aureus infections and to compare the clinical outcomes of Vibrio vulnificus, methicillin-resistant Staphylococcus aureus, and methicillin-sensitive Staphylococcus aureus necrotizing infections. METHODS One hundred and fifteen patients with necrotizing fasciitis caused by Vibrio vulnificus (sixty patients) or Staphylococcus aureus (fifty-five patients) were retrospectively reviewed over a six-year period. Differences in mortality, patient characteristics, clinical presentations, laboratory data, and hospital course were compared between the Vibrio vulnificus and Staphylococcus aureus groups. RESULTS Nineteen patients (including eleven in the Vibrio vulnificus group and eight in the Staphylococcus aureus group) died, resulting in a mortality rate of 16.5%. We found significant differences between the two groups with regard to hypotension, fever, the interval between contact and admission, the interval between the diagnosis of necrotizing fasciitis and the first operation, and admission to the intensive care unit. The patients in the Vibrio vulnificus group had significantly lower total white blood-cell counts, higher banded white blood-cell counts, and lower platelet counts as compared with those in the Staphylococcus aureus group. The proportion of patients who were hypotensive (as indicated by a systolic blood pressure of ≤ 90 mm Hg) was significantly greater in the methicillin-resistant Staphylococcus aureus subgroup than in the methicillin-sensitive Staphylococcus aureus subgroup. Patients with hepatic dysfunction were significantly more likely to have Vibrio vulnificus infection, and those with diabetes mellitus were significantly more likely to have Staphylococcus aureus infection. CONCLUSIONS Necrotizing fasciitis caused by Vibrio vulnificus and Staphylococcus aureus is a surgical emergency. Vibrio vulnificus infection progresses more rapidly and the clinical characteristics are more fulminant than either methicillin-resistant Staphylococcus aureus or methicillin-sensitive Staphylococcus aureus infection.