The role of serum anti-neuraminidase antibody in resistance to influenzal illness was investigated by administration of wild-type influenza A/Hong Kong/1968 (H3N2) virus to volunteers who possessed varying levels of this antibody but who lacked antibody for the hemagglutinin surface antigen of the virus. Clinical response to the wild-type virus was related to the level of serum anti-neuraminidase antibody. Volunteers in whom influenzal disease with fever developed possessed low levels of serum antibody prior to challenge, whereas men who underwent inapparent infection had a significantly higher mean level of antibody for neuraminidase. Those with afebrile illness had an intermediate level of anti-neuraminidase antibody. Duration of virus excretion and maximal level of virus shed were also inversely related to the titer of serum anti-neuraminidase antibody. These findings provide evidence that antibody directed against influenzal neuraminidase is associated with resistance to clinical expression of influenza A virus in man.