Background: Chronic rhinosinusitis with and without nasal polyps (CRSwNP/ CRSsNP) is an inflammatory disease affecting the nasal and sinus mucosal lining. Here, to further characterize this heterogeneous disease, we performed an extended endotyping of CRS using the nasal tissue from CRS-patients and a new approach of expression profiling of chemokines related to Th2-type cytokine IL-5. Methods: In this case-control study, we included 66 patients with CRS (CRSwNP n=26; CRSsNP n=40) diagnosed according to the EPOS 2020 criteria. The control group (n=25) consisted of CRS-free patients scheduled for inferior turbinate surgery. The concentration of following chemokines and cytokines was determined in tissue samples obtained during routine surgery from all subjects: TARC/ CCL17, PARC/ CCL18, eotaxin/ CCL11, MCP-3/ CCL7, MIP-1α/ CCL3, IP-10/ CXCL10, ENA-78/ CCL5, and IL-5. The analysis was performed by partition-based clustering. Results: In CRS tissues, the concentration of eotaxin, TARC, total IgE, IL-5, and ECP was significantly higher than in control (p<0.005). The analysis identified seven clusters. Cluster-1 was IL-5- and inflammatory chemokines-negative (11% CRSwNP). Cluster-2 had low IL-5 concentration and elevated MCP-3/CCL7 (100% CRSsNP). Clusters -3 and -4 expressed IP-10/CXCL10 (type-1-dominated), TARC/CCL17 and eotaxin/CCL11 (both type-2-dominated) (CRSwNP 13-31%). Clusters 5-7 had high concentration of IL-5, TARC/ CCL17, PARC/ CCL18, and eotaxin/CCL11 (type-2-dominated), NP 71-100%, asthma 19-50%, N-ERD 29%. Conclusions: Our chemokine expression-based extended analysis identified distinct CRS endotype clusters, possibly impacting future diagnosis, monitoring, and biologics-based treatment of CRS.