Enterobacter sakazakii (ES) causes invasive infections in newborns that are rare but have a high case-fatality rate. In early December 2004, the French Institute for Public Health Surveillance was notified of invasive ES infections in three newborns at two hospitals; all had consumed the same powdered infant formula (Pregestimil®). The investigation aimed to assess the extent of the outbreak, confirm its source, and implement control measures. Case identification focused on maternity wards, neonatal units, and pediatric wards. A case was defined as any hospitalized newborn from whom E. sakazakii was isolated on or after January 1, 2004, from a sterile site (invasive infection) or a non-sterile site (non-invasive infection or colonization, depending on associated clinical signs). A descriptive case study, a foodborne investigation, testing for ES in Pregestimil® samples, and a comparison of the isolated ES strains were conducted. Four infections (2 cases of meningitis resulting in death, 1 case of hemorrhagic colitis, 1 case of conjunctivitis) and 5 colonizations occurred in 5 hospitals between weeks 44 and 51; 8 newborns were preterm or had low birth weight. All were receiving Pregestimil®. ES was isolated from 31 unopened containers from the Pregestimil® batches consumed by the cases. The strains isolated from the cases or from the batches were not distinguishable by pulsed-field gel electrophoresis. Only one of the 5 hospitals had major breaches of hygiene procedures in the infant feeding unit. In all hospitals, reconstituted preparations were used within 24 hours but were often stored in refrigerators at uncontrolled temperatures or > 4 °C. Hospital environmental samples were negative for ES. No other cases were reported by European countries notified via the Early Warning and Response System (EWRS). These are the first cluster of ES infections in France associated with a contaminated infant formula powder, leading to a product recall. Healthcare professionals should be aware that these powdered formulas are not sterile and must be used and handled with care. In France, hygiene recommendations for the preparation and storage of baby bottles have been developed since this incident by the French Food Safety Agency (AFSSA). (R.A.)