Epidemic influenza occurs annually throughout the world and is accompanied by excess morbidity and mortality. Increasing the antigen content and topical administration of vaccine are two strategies being explored to improve the immune responses to trivalent inactivated influenza vaccine (TIV). We conducted a randomized, double-blind, placebo-controlled trial to compare the immunogenicity and reactogenicity of intramuscular (IM), intranasal (IN), or combined IM and IN administration of a contemporary US vaccine formulation at escalating dosage levels in young healthy adults. Two hundred forty three healthy adults between the ages of 18 and 45 years received 15, 30, or 60mcg of trivalent inactivated influenza vaccine by either IN, IM or both routes, 120mcg of vaccine IM, or placebo IN and IM. All dosages and routes of vaccine administration were well-tolerated. A bad taste and mild nasal discomfort were more likely to be reported when influenza vaccine was administered IN, while arm tenderness was more common after IM administration. Significant increases in geometric mean serum antibody titers in both HAI and Nt assays were seen in all of the groups receiving influenza vaccine for all test antigens (P<or=.025, paired t-test), except for the B HAI antibody titer in the group that received 30mcg IN (P=.055, paired t-test). Postvaccination geometric mean serum antibody titers, the frequency of seroresponses, and the percentage achieving postvaccination serum HAI antibody titers of >or=32 were higher following delivery of the study vaccines by an IM route than by the IN route, but significant increases in serum antibody were seen after IN vaccination. Nasal IgA antibody responses were more common when vaccine was administered IN; and, when the IN dosage was increased, the primary benefit from IN vaccine over IM vaccine appeared to be greater induction of nasal secretory antibody.