AbstractHeadache is a common symptom of influenza infection; however, its causes and consequences remain uncertain. In this manuscript, we analyzed which demographic and clinical factors were associated with the presence of headache during the course of influenza infection and whether patients with headache had a different prognosis, evaluated by need of hospitalization, sick leave or school absenteeism. The influence study (NCT05704335) was an observational study that analyzed data routinely collected from the Health Sentinel Network between 2010 and 2020. During the study period, 7832 cases were considered, among which, 5275 (67.4%) reported headache. The presence of headache was independently associated with myalgia (2.753; 95%CI: 2.456–3.087, P < 0.001), asthenia (OR: 1.958; 95%CI: 1.732–2.214, P < 0.001), shivering (OR: 1.925; 95%CI: 1.718–2.156, P < 0.001), nasopharyngeal erythema (OR: 1.505; 95%CI: 1.293–1.753, P < 0.001), fever (OR: 1.469; 95%CI: 1.159–1.861; P = 0.001), sudden onset of symptoms (OR: 1.380; 95%CI: 1.120–1.702, p = 0.004), female sex (OR: 1.134; 95%CI: 1.023–1.257, P = 0.018), and gastrointestinal symptoms (OR: 1.169; 95%CI: 1.039–1.315; P = 0.01). Patients with headache had a sex and age adjusted lower odds of being referred to the hospital (OR: 0.463; 95%CI: 0.264–0.812, P = 0.007) and a higher odd of having a sick leave and/or school absenteeism (absenteeism (OR: 1.342; 95%CI: 1.190–1.514, P < 0.001). In conclusion, the presence of headache seems associated with symptoms caused by the innate immune response. These findings support a headache pathophysiology linked with the innate immune response. Due to the potential negative consequences and its treatable nature, clinicians should systematically evaluate it and, whenever necessary, treat it too.