Post-mortem investigation in cases of fatal anaphylaxis is required to provide clarifications on the presence of macroscopic pathological changes, histological features, and immunohistochemical positivity suggestive of the diagnosis, on biochemical evidence of anaphylaxis and on the presence of serological data indicative of the allergen responsible for the anaphylactic reaction. We describe the case of a 16-year-old boy with a medical history of allergic asthma, celiac disease, and known food-induced allergy for fish, fresh milk, peanuts, hazelnuts, walnuts, apples, kiwis, and peaches. Acute onset of dyspnea followed by cyanosis of the lips and respiratory failure was described immediately after having an ice cream sandwich. Unsuccessful rescues were immediately attempted with oral administration of betamethasone, intramuscular injection of adrenaline, and cardiopulmonary resuscitation. A complete post-mortem examination was performed. Serum dosage of mast cell beta-tryptase from femoral blood detecting serum values of 41.4 mg/l. Determination of specific IgE on cadaveric blood samples confirmed the anamnestic data related to sensitization for several food allergens, including cod parvalbumin, tropomyosin, brazil nut, omega-5-gliadin of foods derived from wheat and gluten. The cause of death was identified in a cardiorespiratory failure due to anaphylactic shock in a poly-allergic subject and anaphylaxis was ascribed to the wheat contained in the ice cream sandwich eaten immediately before the onset of respiratory symptoms. The need is to implement an interdisciplinary approach capable to ascertain the sensitivity and specificity of the diagnostic tests currently in use as well as to evaluate the possibility of introducing new biomarkers in practice.