Chronic rhinosinusitis (CRS) may be the primary presenting symptom for primary immunodeficiencies (PID). PID can affect the humoral or the cellular immune system. This paper provides an overview of PID which affect the humoral immune system, with details around the diagnostic criteria, the epidemiology, the subtypes, the clinical manifestations, underlying molecular mechanisms, methods to screen for PID and the management of CRS in the context of PID. A high clinical suspicion of PID is required when assessing patients with CRS who are refractory to maximal medical therapy.