Background Topical nasal decongestant sprays are used commonly in routine otolaryngology practice to reduce the symptoms of nasal airway obstruction (NAO) through vasoconstriction, thereby reducing the bulk of vasoerectile tissue and increasing nasal airflow. Such tissue is found predominantly on the lateral wall of the nose within the inferior turbinates (ITs), but recent evidence suggests that it may also be found medially within the nasal septal swell body (SSB). Objective To determine whether isolated topical decongestion of the medial nasal wall, targeting the SSB, is as effective as isolated decongestion of the lateral nasal wall, targeting the IT, in maximizing nasal patency. Methods A double-blinded, randomized controlled, crossover study was performed investigating the effect of decongestion of the lateral nasal wall or septum in isolation on nasal airflow. Isolated decongestion was performed by placing a cottonoid, soaked in oxymetazoline and attached to a silastic sheet, into the nasal cavity randomly facing either the septum or lateral nasal wall, bilaterally. Anterior rhinomanometry, acoustic rhinometry, peak nasal inspiratory flow (PNIF), and subjective patient-reported outcomes (Sinonasal Outcome Test (SNOT-22) and Nasal Obstruction Symptom Evaluation (NOSE) scores) were recorded at baseline and postdecongestion. Decongestion of the alternate site was then performed at a later date. Results A total of 20 healthy volunteers (30% females, mean age 26.6 ± 3.8 years) were recruited. Improvements in nasal obstruction and SNOT-22 scores were found following decongestion of the septum compared with baseline (mean difference: 0.82, t = 2.32, P = .04; mean difference: 3.30, t = 2.50, P = .04, respectively). Improvements in mean inspiratory flow, minimal cross-sectional area, volume, and PNIF were also demonstrated. Conclusion This study suggests that the SSB contains erectile tissue that responds to topical decongestant therapy in a similar manner to IT tissue. The SSB may represent a novel target in surgery for NAO.