Rationale Examine the efficacy and safety of a single dose of R926112, an inhibitor of the tyrosine kinase Syk critical for mast cell signaling, on symptoms, mediator release, and nasal volumes in allergic rhinitis. Methods Twenty out-of-season volunteers with grass or ragweed pollen induced allergic rhinitis were enrolled in this double blind randomized crossover trial. Subjects underwent a screening nasal allergen challenge to establish the extract dose eliciting a Bousquet score of 5. One dose of R926112 or vehicle was given intranasally followed by nasal allergen challenge 15 minutes later. Symptom scores were obtained at baseline, after treatment and after challenge. Histamine and PGD 2 content of nasal secretions was determined at baseline, 5 and 10 minutes, and tryptase content at baseline and 10 minutes after allergen challenge. Bilateral nasal volumes (cm 3 ) and minimal cross sectional area (MCA) were assessed by acoustic rhinometry before and twenty minutes after challenge. Results Adverse event frequency was similar between treatments. R926112 resulted in a significant decrease in PGD 2 at 5 minutes vs. vehicle (93.4 ± 23 pg/ml vs . 171.6 ± 23 pg/ml p=0.03) that correlated with rhinorrhea (p=0.05). PGD 2 and tryptase at 10 minutes tended to decrease with R926112 administration (46.8 ± 9.2 pg/ml vs . 68.6 ± 9.2 p=0.1, and 9.5 ± 2.7 ng/ml vs . 16.6 ± 2.9, p=0.09). Treatment improved rhinorrhea but symptom scores were not significantly different between groups. There were no differences in histamine concentrations between the treatment arms or acoustic rhinometry determined volume or cross-sectional area. Conclusions R926112 appears to be safe and reduces mediator release in subjects with allergic rhinitis.