BACKGROUND CRX-675 is an aqueous formulation of a toll-like receptor 4 agonist and an inducer of TH1 responses. Studies in allergic dogs showed that pretreatment with CRX-675 reduced nasal congestion induced by allergen challenge. OBJECTIVE To study the safety of intranasal CRX-675 treatment in patients with seasonal allergic rhinitis. METHODS We conducted a single-center, randomized, double-blind, placebo-controlled, dose-escalating safety trial of single doses of CRX-675 given intranasally before intranasal ragweed challenges. Patients with ragweed-induced seasonal allergic rhinitis received increasing concentrations of ragweed to determine the dose that would result in a 30% reduction in nasal volume (PD30) during screening. Two weeks later, each patient was rechallenged with their assigned PD30 ragweed dose. Fourteen days later, patients were treated with either placebo (n = 16) or CRX-675 (2, 20, 100, or 200 microg intranasally, n = 12 per arm) 24 hours before a subsequent PD30 ragweed challenge. Patients were rechallenged with ragweed 14 days thereafter. RESULTS No serious or severe adverse events were reported. Most adverse events were mild (grade 1) and either were considered unrelated to CRX-675 or resolved without intervention. The adverse event profile of CRX-675-treated patients was similar to that of placebo-treated patients, and no dose-related toxic effects were observed. There was no clear trend in the ability of CRX-675 to inhibit nasal allergen challenge responses, but improvement in nasal symptom scores was observed at 100 microg. CONCLUSIONS This preliminary trial suggests that intranasally applied CRX-675 is safe at the doses tested. Appropriate dosing and timing will ultimately define its potential therapeutic role for allergies.