A variety of systemic conditions impact the incidence, severity, prognosis, and treatment approach in patients with chronic rhinosinusitis (CRS). The controversy surrounding the impact of allergic rhinitis on CRS continues, but it is reasonable to consider and treat allergic sources of inflammation in any patient with CRS. CRS is more severe in patients with aspirin sensitivity but improves--at least temporarily--to the same degree as in non-aspirin-sensitive patients, given appropriate therapy. Polypoid rhinosinusitis in cystic fibrosis patients is characterized by compromised mucociliary clearance and infection with staphylococcal and pseudomonal organisms. Affected individuals require frequent antibiotic treatment, saline lavage, and repeated surgeries. Rhinosinusitis is among the most common infectious complications of humoral immunodeficiency, which is not uncommon in patients with refractory CRS. The treatment approach in immunodeficiency includes aggressive antibiotic treatment and intravenous immunoglobulin. Specific diagnosis of comorbid systemic conditions with CRS will facilitate appropriate management.