Rationale Saline nasal sprays are frequently used in the management of seasonal allergic rhinitis (SAR) for the cleansing and clearing of aeroallergens from the nasal cavity. Also using a drug-free approach, AM-301 nasal spray is forming a thin film barrier on the nasal mucosa to prevent contact with allergens, trap them, and facilitate their discharge. A clinical trial compared the efficacy, safety, and tolerability of AM-301 and saline spray in SAR. Methods A total of 100 patients were randomized 1:1 to self-administer AM-301 or saline 3 × daily for 2 weeks. Primary efficacy endpoint: reduction in mean daily reflective Total Nasal Symptom Score (rTNSS). Secondary efficacy endpoints: reduction in mean instantaneous TNSS and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), global impression of efficacy. Safety and tolerability: adverse events, relief medication use, symptom-free days, global impression of tolerability. Results AM-301-treated patients achieved a significantly lower rTNSS than the saline group (LS square means difference −1.1, 95% CI −1.959 to −0.241, p = .013) with improvement observed across all individual nasal symptoms. Likewise, all secondary endpoints showed statistical significance in favor of AM-301; for example, quality of life was significantly improved overall (p < .001) as well as for each individual RQLQ domain. Both treatments showed similarly good safety and tolerability. With AM-301, fewer patients used relief medication and more enjoyed symptom-free days compared to saline treatment. Conclusions AM-301 was more effective than saline in improving SAR nasal symptoms and related quality of life while offering similar tolerability, demonstrating the benefits of a barrier approach.