There is published evidence that cetirizine has a longer duration of effect than fexofenadine. This study compared duration of effect and other measures of efficacy of cetirizine, 10 mg; fexofenadine, 180 mg; and placebo in allergic subjects exposed to pollen in the Environmental Exposure Unit. Eligible subjects (n = 575) were exposed to ragweed pollen (day 1, 7 hours; day 2, 5 hours) and randomized in double-blind fashion to once-daily cetirizine, 10 mg; fexofenadine, 180 mg; or placebo. The total symptom severity complex (TSSC) score, the primary efficacy variable, was based on four rhinoconjunctivitis symptoms rated at 20-minute intervals. Treatment evaluation was divided into three periods: period 1 TSSC, average of 15 scores obtained 0-5 hours after the first dose; period 2 TSSC, average of 9 scores obtained 21-24 hours after the first dose; and period 3 TSSC, average of 6 scores obtained 0-2 hours after the second dose. The primary efficacy end point was the change from baseline TSSC at period 2. Baseline TSSC was the final pretreatment score on day 1 and was 9.7 for cetirizine, 9.8 for fexofenadine, and 9.7 for placebo. For the primary efficacy end point, the reduction in baseline TSSC at period 2 was greater for cetirizine (-3.6) compared with fexofenadine (-2.7; p < 0.001) and placebo (-2.0; p < 0.001), representing a 33% greater reduction for cetirizine versus fexofenadine. Cetirizine continued to reduce TSSC more than fexofenadine (-5.2 versus -4.6; p = 0.017) and placebo (-3.9; p < 0.001) (period 3). Similar efficacy was observed in period 1 for both active treatments. Treatment-related adverse events were similar in all groups with an incidence of somnolence of 1.3% for both active medications. In conclusion, cetirizine produced a 33% greater reduction in SAR symptoms over the 21- to 24-hour interval after the first dose and for 40 minutes after the second dose, indicating a superior and longer duration of effect, which is relevant because both are once-daily medications. Onset of action was comparable and both treatments were safe and well tolerated.