<b><i>Background:</i></b> No comparative study of antihistamines that differ in structural system has been conducted in allergic rhinitis. <b><i>Objective:</i></b> This was a randomized, double-blind, crossover comparative study to verify the efficacy of antihistamines that differ in structural system. <b><i>Methods:</i></b> A total of 50 patients with moderate or more severe Japanese cedar pollen-induced allergic rhinitis were randomized to receive either placebo, desloratadine 5 mg (a tricyclic), or levocetirizine 5 mg (a piperazine). One dose of the study drug was orally administered at 9 pm on the day before a pollen exposure test, which was performed for 3 h (9 a.m. to 12 p.m.) to assess symptoms in an environmental challenge chamber (ECC). Nasal and ocular symptoms were compared at an airborne pollen level of 8,000 grains/m³. The primary endpoint was mean total nasal symptom score (TNSS) from 120 to 180 min in the ECC. Subjects with a difference of ≥1 in TNSS between 2 drugs were extracted to the relevant drug-responsive group. <b><i>Results:</i></b> The difference in TNSS from placebo was –2.42 (<i>p</i> &#x3c; 0.0001) with levocetirizine and –1.66 (<i>p</i> &#x3c; 0.01) with desloratadine, showing that both drugs were significantly more effective than placebo in controlling symptoms, but with no statistically significant difference between the 2 drugs. There were 12 subjects in the desloratadine-responsive group and 24 subjects in the levocetirizine-responsive group, with no contributor to response was detected. <b><i>Conclusion:</i></b> Levocetirizine tended to control nasal symptoms more effectively than desloratadine. However, the response to each antihistamine varied among individuals and the predictors to the response are unknown. <b><i>Clinical Trial Registration number:</i></b> UMIN ID: UMIN000029653.

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