Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease. No medications are Food and Drug Administration-approved for the most common form, CRS without nasal polyps (also called "chronic sinusitis"). Novel biomechanics of the exhalation delivery system deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard-delivery nasal sprays. Assess EDS-FLU efficacy for CRS (irrespective of nasal polyps). Two randomized, EDS-placebo-controlled trials in adults with CRS irrespective of polyps (ReOpen1) or exclusively without polyps (ReOpen2) were conducted at 120 sites in 13 countries. Patients received EDS-FLU 1 or 2 sprays/nostril, or EDS-placebo, twice daily for 24 weeks. Coprimary measures were composite symptom score through week 4 and ethmoid/maxillary sinus percent opacification by computed tomography at week24. ReOpen1 (N= 332) composite symptom score least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was-1.58 and-1.60 versus-0.62 (P < .001, P < .001); ReOpen2 (N= 223),-1.54 and-1.74 versus-0.81 (P= .011, P= .001). In ReOpen1, sinus opacification least-squares mean change for EDS-FLU 1 or 2 sprays/nostril versus EDS-placebo was-5.58 and-6.20 versus-1.60 (P= .045, P= .018), and in ReOpen2,-7.00 and-5.14 versus+1.19 (P< .001, P= .009). Acute disease exacerbations were reduced by 56% to 66% with EDS-FLU versus EDS-placebo (P= .001). There were significant, and similar magnitude, symptom reductions in patients using standard-delivery nasal steroid products just before entering the study (P < .001). Adverseevents were similar to standard-delivery intranasal steroids. EDS-FLU is the first nonsurgical treatment demonstrated to reduce symptoms, intrasinus opacification, and exacerbations in replicate randomized clinical trials in CRS, regardless of polyp status.