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Background: To assess the risk of depression in patients with chronic rhinosinusitis (CRS) in a tertiary care center and the effect of treatment on depression scores. Methods: This prospective cohort study was conducted at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, between November 2021 and June 2022 and included adult patients (≥14 years) with CRS. The validated Arabic or English Sinonasal Outcome Test (SNOT-22) and Patient Health Questionnaire-9 (PHQ-9) were used before treatment and 3 to 6 months after surgery and maximal medical treatment. PHQ-9 scores were compared at baseline and follow-up visits. The relationship between changes in SNOT-22 and PHQ-9 scores were assessed using Spearman's correlation and simple linear regression. Results: Overall, 38 participants with a mean ± SD age of 32.7 ± 12 years were enrolled. CRS with nasal polyps (55.26%) was the most frequently seen condition, followed by allergic fungal CRS (31.58%) and CRS without nasal polyps (13.16%). Six patients (15.7%) had PHQ-9 scores ≥10, indicating they had major depressive disorder. PHQ-9 and SNOT-22 scores improved significantly after treatment (3.7 ± 5.8 vs 6.5 ± 6.9 pretreatment, P =.001; 20.7 ± 20.5 vs 45.6 ± 28.9 pretreatment, P <.0001, respectively). Mean ± SD change in PHQ-9 and SNOT-22 scores was −2.7 ± 7 and −24.9 ± 29.8, respectively. SNOT-22 and PHQ-9 scores were positively correlated (r =.522, P <.001). PHQ-9 score change was significantly associated with SNOT-22 score change (β =.178, 95% confidence interval 0.12-0.23, P <.0001). Conclusion: CRS affects the quality of life and psychological well-being of patients. Patient-centered care with maximal medical and surgical treatment help overcome its deleterious consequences. [ABSTRACT FROM AUTHOR]