Understanding of the role played by mast cells in allergic rhinitis (AR) has led to the development of novel therapies. The aim of this study was to determine the safety and tolerability of R112, an inhibitor of the tyrosine kinase Syk, in an allergen challenge model of AR. We also examined the effects of R112 on symptoms, mediator release, and nasal airway volumes. This double-blinded, randomized, placebo-controlled, crossover trial enrolled 20 out-of-season volunteers with AR. One intranasal dose of R112 or vehicle was administered and followed by an allergen challenge. In addition to safety monitoring, symptoms; changes in histamine, tryptase, and prostaglandin D2 (PGD2) content of nasal secretions; and acoustic rhinometry were determined over a 15-minute period. R112 was well tolerated. Adverse events were similar between treatments. Five minutes after allergen instillation, PGD2 was decreased when subjects received R112 compared with vehicle (93.4±23.0 pg/mL versus 171.6±23.0 pg/mL; p= 0.03), and this correlated with rhinorrhea (p= 0.05). However, at 10 minutes, changes in PGD₂, tryptase, and histamine were not significant (46.8±9.2 pg/mL versus 68.6±9.2 pg/mL, p= 0.1; 9.5±2.7 ng/mL versus 16.6±2.9 ng/mL, p= 0.09; and 1.5±1.6 ng/mL versus 3.5±1.6 ng/mL, p= 0.4). No differences were found in symptoms or in acoustic rhinometry between treatment groups. Single-dose R112 appears safe and significantly reduces PGD₂ but not histamine or tryptase release in response to allergen challenge in subjects with AR.