Azelastine nasal spray is commercially available as a 0.1% w/v solution and is recommended for twice-daily dosing. Increasing the azelastine concentration to 0.15% may be effective with once-daily dosing without increasing the incidence of adverse events. This study evaluated the efficacy and safety of azelastine 0.15% nasal spray at a dosage of 2 sprays/nostril once daily. This randomized, double-blind, placebo-controlled study was conducted in subjects with moderate-to-severe seasonal allergic rhinitis (SAR) during the 2007/2008 Texas Mountain Cedar season. In total, 536 subjects were randomized to 2 sprays/nostril once daily (A.M.) of azelastine 0.15% or placebo. The primary efficacy variable was change from baseline in a 12-hour reflective Total Nasal Symptom Score (TNSS), consisting of nasal congestion, runny nose, itchy nose, and sneezing. The key secondary variable was change from baseline in 24-hour instantaneous TNSS, which determines the duration of action and effective dosing interval. After 2 weeks, the mean improvement in 12-hour reflective TNSS and percentage improvement in 12-hour reflective TNSS were significant (p < 0.001) with azelastine 0.15% (19%) compared with placebo (10%). The improvement in 24-hour instantaneous TNSS also was significant (p < 0.001) for azelastine 0.15% compared with placebo, supporting efficacy with once-daily dosing. All individual TNSS symptoms were significantly (p < 0.01) improved with azelastine 0.15% compared with placebo. With the exception of bitter taste (4.5%) and nasal discomfort (4.5%), adverse events with azelastine 0.15% were reported with an incidence similar to placebo. Azelastine 0.15% nasal spray was effective and well tolerated in subjects with SAR with once-daily dosing.