Objectives/Hypothesis There are variants of chronic rhinosinusitis ( CRS ). Therefore, the objectives of this study were to phenotype the subclasses of CRS as well as characterize their polyps with histology and cellular–intracellular biomarkers. Study Design Prospective case‐control study. Methods Demographic data, quality‐of‐life ( QoL ) questionnaires, nasal endoscopy ( NE ), and computed tomography ( CT ) scores were obtained. CRS was divided into seven subclasses: aspirin‐exacerbated respiratory disease ( AERD ), asthmatic sinusitis with and without allergy, nonasthmatic sinusitis with and without allergy, allergic fungal sinusitis ( AFS ), and cystic fibrosis ( CF ). Histopathologic and immunohistochemistry of nasal polyps were recorded. CD3 , CD4 , CD8 , CD19 , CD45 , and CD56 data were collected. Interleukin ( IL )4, IL5 , IL13 , IL17 , and interferon ( IFN )‐γ were measured. Results Eight‐four subjects were in this study. Two QoL questionnaires were inadequate at distinguishing the control group from CRS . NE and CT were able to differentiate between the control group and all CRS subclasses ( P <.01). Asthmatic sinusitis, AERD , and AFS had high NE and CT scores, nasal polyps, eosinophils, mast cell, and hypercellularity. Asthmatic sinusitis, nonasthmatic sinusitis, and AERD had higher CD4 cells than control group ( P <.05). Even though asthmatic sinusitis and AFS are mediated by Th2 , AFS had differing levels of Th2 cytokines. Each nonasthmatic sinusitis had purulence and low CT score. Each nonasthmatic sinusitis had higher CD4 cells and IFN ‐γ than control ( P <.05). CF is associated with purulence, high CT score, high polymorphonuclear leukocytes, high plasma cells, and high mast cells. Conclusions Well‐characterized and distinct groups of CRS have been defined for targeted treatment and research studies. Level of Evidence 2b Laryngoscope , 123:S15–S27, 2013