Following a report, widely covered by the media in February 2014, of students feeling unwell at a middle school in the Aquitaine region that had been undergoing renovation since 2011, an epidemiological and environmental investigation revealed inadequate ventilation in the classrooms. Despite the measures implemented, new symptoms, primarily headaches, emerged in late March 2014, leading to the intervention of the fire department and the closure of the middle school. Given the number of children affected, the worsening of symptoms, and parents’ concerns, a new investigation was conducted. A health coordination unit, led by the French Institute for Public Health Surveillance (renamed Santé publique France in 2016) and the Regional Health Agency, established five assessment components (epidemiological, clinical, environmental, toxicological, and socio-anthropological) and a communication component. The investigation made it possible to characterize the symptoms in terms of frequency, severity, and timing; to contribute to clinical management; to identify potential pollutants causing the symptoms; and to assess the experiences of students, their parents, and staff since the start of the construction work. Data on school absences and visits to the infirmary indicated that symptoms began in January 2014 among students and, according to a cross-sectional survey, among staff since the start of construction. The lack of severity was confirmed by clinical assessment, with medical care provided to students as needed. Toxicological analysis showed that the pollutants detected could cause discomfort or irritation, but posed no short- or long-term risk. The socio-anthropological analysis highlighted strained relationships between institutional decision-makers, staff, sports association representatives, and parents since the start of construction. The investigation concluded that a multifactorial collective syndrome was present, characterized by the unusual onset of non-serious symptoms beginning in early 2014 among certain students and teachers. The measures implemented successfully curbed the occurrence of symptoms, with no new cases reported at the start of the 2014–2015 school year. Apart from the difficulties inherent in this type of incident, multidisciplinary expertise and cross-disciplinary perspectives helped clarify the situation and implement appropriate measures. The inclusion of a communication component throughout the incident ensured consistency in the information received by partners, parents, and students.