Twenty-six volunteer subjects were challenged intranasally with parainfluenza virus type 2. Their response to the challenge was evaluated with respect to the prechallenge serum and nasal neutralizing activity against the infecting virus. Ninety-two per cent of the individuals possessed prechallenge serum antibody to the virus, and 42% had neutralizing activity in the nasal wash specimen. Following challenge, 14 of the volunteers became infected. Illness occurred in 29% of infected persons as an all-or-nothing phenomenon, independent of virus shedding. Nasal antibody prevented infection or markedly reduced virus shedding. Serum antibody was effective in reducing infection in direct relation to the height of the titer, but if nasal antibody was present the effect was augmented about fourfold. A serologic antibody response was the most sensitive index of infection. The most demonstrable effect of antibody was the reduction of illness, then virus shedding. Increasing immunity to infection was found with 1) a low titer of serum antibody alone, 2) low serum antibody plus nasal antibody and 3) a high titer of serum antibody. No infection occurred in a small number of subjects with high titers of serum antibody plus neutralizing activity in the nasal secretions.