Fexofenadine HCl (Allegra, Telfast) is approved in the US for twice-daily dosing in the treatment of seasonal allergic rhinitis (SAR). A once-daily dose (already available in some countries outside the US) can improve patient compliance and health outcomes. This multicenter, placebo-controlled, 14-day US study was conducted to compare the safety and effectiveness of once-daily fexofenadine HCl with placebo in the treatment of patients with moderate to severe autumnal SAR symptoms. After a 1-week placebo lead-in, patients received 120 or 180 mg fexofenadine HCl or placebo at 8 A.M. Patients recorded SAR symptom severity scores instantaneously (for the 1 hour before medication; i.e., trough blood levels), and reflectively (for the previous 12 hours) at 8 A.M. and 8 P.M. The primary efficacy measure was change from baseline in average instantaneous 8 A.M. total symptom score (TSS, the sum of individual symptom scores excluding nasal congestion). In 861 intent-to-treat patients, both fexofenadine HCl doses provided significant (p < or = 0.05) improvement in 8 A.M. instantaneous TSS compared with placebo. Similarly, both fexofenadine doses were superior to placebo for reflective TSS assessments (p < or = 0.0012). There were no statistical differences in efficacy between the two fexofenadine doses, though the 180 mg dose showed a trend toward greater symptom relief. Incidence of adverse events was similar between fexofenadine and placebo groups (30.2% and 30.0%, respectively), with headache the most frequently reported adverse event (8.9% and 7.5%, respectively). In conclusion, once-daily fexofenadine HCl, 120 or 180 mg, is safe and effective in the treatment of autumnal SAR.