Summary Background There are no data directly comparing the relative efficacy of modern H(1)-antihistamines in allergic rhinitis using nasal provocation challenge. Objective We elected to study the comparative effectiveness of usual clinically recommended doses of desloratadine (DES), fexofenadine (FEX), and levocetirizine (LEV), on nasal adenosine monophosphate (AMP) challenge in patients with perennial allergic rhinitis (PAR). Methods 16 patients with PAR were randomized in double-blind cross-over fashion to receive single doses of DES 5 mg, FEX 180 mg, LEV 5 mg, or placebo (PL), with nasal AMP challenge performed 12 h after dosing. Measurements of peak nasal inspiratory flow (PNIF) were made over 60 min after nasal AMP challenge. Results Pre-challenge values (mean+/-SEM) for PNIF (L/min) were not significantly different comparing all groups; DES (129+/-9), FEX (128+/-11), LEV (128+/-13), and PL (128+/-12). The maximum % PNIF fall from baseline over 60 min after nasal AMP challenge was significantly attenuated (P<0.05) compared to PL (50+/-4), with DES (32+/-5), FEX (36+/-4), and LEV (36+/-4). The area under the 60-min time-response curve (%.min) was also significantly attenuated (P<0.05) compared to PL (2110+/-268), with DES (1126+/-285), FEX (1225+/-255), and LEV (1261+/-194). There were no significant differences between the three H(1)-antihistamines for any outcomes. Conclusion DES, FEX, and LEV were equally effective in attenuating the response to nasal AMP challenge. However, further long-term studies will be required to study their comparative effects on nasal symptoms, quality of life, as well as on nasal inflammatory cells.