Oxymetazoline relieves nasal obstructive symptoms via vasoconstriction, however, the changes in nasal structures and aerodynamics that impact symptoms the most remain unclear. This prospective, longitudinal, and single blinded cohort study applied Computational Fluid Dynamic (CFD) modeling based on CT scans at baseline and post-oxymetazoline on 13 consecutive patients with chronic nasal obstruction secondary to inferior turbinate hypertrophy from a tertiary medical center. To account for placebo effect, a sham saline spray was administered with subject blindfolded prior to oxymetazoline, with 30 min rest in between. Nasal Obstruction Symptom Evaluation (NOSE) and unilateral Visual Analogue Scale (VAS) scores of nasal obstructions were collected at baseline, after sham, and 30 min after oxymetazoline. Both VAS and NOSE scores significantly improved from baseline to post-oxymetazoline (NOSE: 62.3 ± 12.4 to 31.5 ± 22.5, p < 0.01; VAS: 5.27 ± 2.63 to 3.85 ± 2.59, p < 0.05), but not significantly from baseline to post-sham. The anatomical effects of oxymetazoline were observed broadly throughout the entire length of the inferior and middle turbinates (p < 0.05). Among many variables that changed significantly post-oxymetazoline, only decreased nasal resistance (spearman r = 0.4, p < 0.05), increased regional flow rates (r = -0.3 to -0.5, p < 0.05) and mucosal cooling heat flux (r = -0.42, p < 0.01) in the inferior but not middle turbinate regions, and nasal valve Wall Shear Stress (WSS r = -0.43, p < 0.05) strongly correlated with symptom improvement. Oxymetazoline broadly affects the inferior and middle turbinates, however, symptomatic improvement appears to be driven more by global nasal resistance and regional increases in airflow rate, mucosal cooling, and WSS, especially near the head of the inferior turbinate. 3: Well-designed, prospective, single blinded cohort trial. Laryngoscope, 134:1100-1106, 2024.