Primary immunodeficiency diseases (PID) comprise over 200 individual conditions. Although quite rare in the US population, a delay in diagnosis may be associated with increased morbidity due to life-threatening infections. Many US states test for some PIDs on newborn screens; however, not all immunodeficiencies will be detected. Therefore, patient advocacy groups are championing an expert opinion–derived diagnostic schema entitled “10 Warning Signs of PID” in order to increase awareness of these conditions. These signs include: (1) ≥4 ear infections within 1 year, (2) ≥2 serious sinus infections within 1 year, (3) ≥2 months of oral antibiotic treatment with little effect, (4) ≥2 episodes of pneumonia within 1 year, (5) failure to thrive, (6) recurrent deep skin or organ abscesses, (7) persistent thrush or fungal skin infection, (8) need for IV antibiotics, (9) ≥2 deep-seated infections, including sepsis, and (10) family history of PID. This study sought to rigorously evaluate the diagnostic efficacy of this schema.