BACKGROUND: To date, no adequate data are available on direct comparison of the efficacy of levocetirizine, a recently approved histamine1-antihistamine, with that of a leukotriene antagonist in the treatment of seasonal allergic rhinitis (SAR) symptoms. OBJECTIVE: To compare the efficacy of therapeutic doses of 5 mg of levocetirizine and 10 mg of montelukast in ragweed sensitized patients. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was conducted between July and October 2006. Symptomatic patients with SAR were exposed to ragweed pollen under controlled conditions in an environmental exposure chamber for 4 to 5 hours after treatment with 5 mg of levocetirizine, 10 mg of montelukast, or matched placebo on 2 consecutive days. The mean change from baseline in pollen-induced rhinitis symptoms, expressed as a major symptoms complex (MSC) score (sum of scores for rhinorrhea, itchy nose, sniffles, nose blows, sneezes, and watery eyes), in period 1 (first 5 hours after first drug intake) was the primary efficacy outcome. RESULTS: A total of 611 patients were screened, of whom 403 were randomized to receive treatment (102 placebo, 152 levocetirizine, and 149 montelukast). The MSC score in period 1 was progressively decreased to a significantly greater extent in the levocetirizine group compared with the montelukast and placebo groups (adjusted mean differences, -2.18 [95% confidence interval, -3.35 to -1.01; P < .001] and -2.22 [95% confidence interval, -3.51 to -0.92; P < .001] for levocetirizine vs montelukast and vs placebo, respectively). The effect of 10 mg of montelukast was not significantly different compared with placebo. Levocetirizine also achieved a significantly faster onset of action within 2.5 hours of administration. Both products were well tolerated. CONCLUSIONS: This study in an environmental exposure chamber confirms the therapeutic efficacy of 5 mg of levocetirizine in improving symptoms of SAR, which was superior to 10 mg of montelukast.