Introduction - The Eneis 3 study aimed to track changes in the incidence of serious adverse events (SAEs) associated with healthcare in healthcare facilities between 2009 and 2019. Method - A national, longitudinal, prospective incidence survey of an open population of full-time hospitalized patients followed for a period of seven days, based on a random sample of public and private healthcare facilities in metropolitan France using a three-stage cluster sampling design (department, facility, care unit) and stratified (internal medicine, surgery). Results - One hundred twenty-three serious adverse events (SAEs) were identified during the follow-up of 4,825 patients over 21,686 observation days. On average, 4.4 serious adverse events (SAEs) (95% confidence interval: 95% CI: [2.9–6.8]) were observed in 2019 per 1,000 hospital days, 34% of which were preventable. SAEs accounted for 2.6% [1.8–3.8] of hospital stays, 53% of which were preventable. Of the 61 SAEs eligible for reporting, only one had been reported at the time of data collection. The incidence rate of preventable SAI occurring during hospitalization decreased statistically between 2009 and 2019. In medicine, a downward trend was observed across all specialties except critical care. In surgery, the incidence rate decreased statistically significantly only in university hospitals (university hospitals). Preventable SAIs related to invasive procedures decreased in interventional sectors, but not for surgical procedures. Preventable SAIs related to health products mainly concern medications, with a similar classification of the highest-risk medications in 2009 and 2019. In contrast, preventable SAIs associated with implantable medical devices (IMDs) remained stable over the period. Preventable SAIs due to healthcare-associated infections also decreased, though this decrease was borderline statistically significant. Factors related to staff working conditions appear to contribute more frequently to the occurrence of SAIs. Discussion-Conclusion - The Eneis 3 study shows a statistically significant decrease in preventable serious adverse events and their severity between 2009 and 2019, but vigilance must be maintained regarding surgery, critical care, and IMDs for events occurring during hospitalization. The worsening of factors contributing to these events appears to stem from improved training of investigators in systemic analysis in 2019, the persistent lack of collaborative practices, and the increased difficulty of working conditions for current healthcare staff. The increase in the proportion of rehospitalizations among serious adverse events (SAEs) leading to hospitalization necessitates continued efforts to ensure safe discharges, particularly in the context of shorter hospital stays. Finally, the underreporting of serious adverse events necessitates strengthening training for healthcare professionals in patient safety. For all these reasons, and in accordance with the conclusions of the 2018 report by the High Council for Public Health (HCSP), patient safety must remain a priority in health policies.