Background. Hypereosinophilic Syndrome (HES) is a rare disorder with an extremely heterogeneous clinical presentation, leading to diagnostic delay, and a very bad prognosis if left untreated. Our study aimed at highlighting the effectiveness and feasibility of a two-tails approach in improving the HES diagnosis in an Italian Immunology excellence university centre. Methods. A retrospective observational single-centre study was conducted. All the patients underwent blood and instrumental tests to highlight HES aetiology and early detect any organ damage. Results: 79 patients (31 females, 39.2%), with a mean age of 54.9 years, were included in the study. 19 (24.1%) patients were diagnosed with reactive HES, 15 (19.0%) with Overlap HES (EGPA), 1 (1.3%) with myeloid-HES, 10 (12.7%) with lymphocytic HES and 8 (10.1%) with idiopathic HES. 63 patients showed involvement of at least two organs: the lung (32/63, 50.7%), the skin (24/63, 38.1%), the bowel (23/63, 36.5%), and the peripheral nervous system (25.4%). Eight patients (8/63, 12.7%) showed a heart involvement. The diagnosis was achieved in 4±1.8 months and no deaths were observed. Conclusion. HE is a common reason for allergists’ and clinical immunologists’ consultations, and the two-tails approach should be implemented from the first evaluation of patients with HE. This will aim at detecting early organ damage and reducing both diagnostic delay and the risk for mistakes in the classification of HES subtypes, thus allowing a prompt and tailored treatment and better outcome.