Co-infection frequency and impact among influenza-associated acute respiratory distress syndrome (ARDS) patients requiring extracorporeal membrane oxygenation (ECMO) are not known. This retrospective, observational analysis concerned data prospectively collected from patients admitted to our medical intensive care unit (ICU) who received ECMO support for influenza-associated ARDS between 2009 and 2016. Co-infection was defined as occurring within 48 hours following ICU admission. Among the 77 ARDS patients requiring ECMO support, 39 (51%) developed co-infections, with Staphylococcus aureus (18 (46%) of the co-infected) being the most prevalent pathogen. Panton–Valentin leukocidin (PVL)-producing S. aureus was isolated from ten patients (56% of S. aureus co-infections and 26% of all co-infections). Except for body mass index, initial disease severity and antibiotic treatment prior to admission, patients with co-infection were comparable to those without. Co-infection was associated with higher in-ICU mortality (62% vs. 29% without; p=0.006), and, on day 60, (median [interquartile range]) fewer ECMO-free days (0 [0–19] vs. 23 [0–46]; p=0.004) and fewer mechanical ventilation-free days (0 [0–0] vs. 6 [0–35]; p=0.003). Multivariable analyses retained age >49 years, pre-ECMO Simplified Acute Physiology Score II >70 and co-infection as independent predictors of hospital mortality. In conclusion, co-infection is frequent in ECMO-treated patients with influenza-associated ARDS, affecting ~50% of them, and is independently associated with poor outcome. S. aureus was the most frequently identified pathogen, with a high rate of PVL-positive S. aureus. Whether specific therapy targeting PVL-producing S. aureus should be given remains to be determined.