A trivalent cold-adapted recombinant (CR) influenza virus vaccine containing types A and B viruses was compared with monovalent vaccines of each virus in a double-blind, placebo-controlled trial. Adults with a wide range of preexisting antibody titers received one 0.5-mL dose intranasally of trivalent vaccine; monovalent A/H1N1, A/H3N2, or B vaccine; or placebo. All vaccines were well tolerated. Serum antibody response frequencies and postvaccination geometric mean antibody titers were similar for recipients of trivalent or the corresponding monovalent vaccine for each of the vaccine components. Stepwise logistic regression analysis of the antibody responses of trivalent vaccine recipients demonstrated that response to one vaccine virus did not adversely affect the likelihood of response to the other viruses. This study failed to find serologic evidence of interference between vaccine viruses, suggesting that trivalent CR influenza virus vaccine may be useful for preventing influenza in adult populations.