Objectives: To evaluate the therapeutic yield of sinonasal irrigation (SNI) using ceftriaxone solution in saline and its impact on quality of life (QoL) scores. Patients & Methods: This multicenter study was assigned to include all patients attending the outpatient clinic with symptoms suggestive of chronic rhinosinusitis (CRS). Patients were diagnosed according to criteria defined by the Rhinosinusitis Task Force. All patients underwent rigid endoscopy and endoscopic findings were graded according to Lund-Kennedy scoring. All patients were asked to complete two quality of life questionnaires: the Rhinosinusitis Disability Index (RSDI) and the chronic sinusitis score (CSS). All patients received bilateral nasal and sinus irrigation using ceftriaxone sodium 1 gm/200 ml normal saline. Then, all patients were allowed to use the same fluid for twice daily nasal irrigation for 6 weeks and reevaluated. Study outcome included clinical evaluation of presenting symptoms, evaluation of QoL questionnaires and endoscopic scoring at the end of 6 weeks of domiciliary irrigation. Results: The study included 700 CRS patients; 450 in Emirate and 250 Egyptian patients. After 6-weeks of irrigation; 220 patients had only minor symptoms (Responders) and 480 patients had varied distribution among other symptoms severity grades (Nonresponders). There was significant difference of the frequency of patients among symptom severity grades between both evaluation sessions. After 6-weeks follow-up, mean Lund-Kennedy scores, total and subscales of RSDI were significantly lower with significantly higher CSS compared to baseline scores of responders. Moreover, responders showed significantly lower Lund-Kennedy scores and RSDI with significantly higher CSS at the end of follow-up compared to non-responders. Conclusion: SNI has a significant role as a therapeutic modality for CRS patients which could be implemented wherein bacterial resistance to systemic antibiotics was encountered or to postpone surgery or in patients who are unfit or refusing surgery. SNI with ceftriaxone-saline solution allowed minimization of clinical manifestations with improvement of QoL scores.