Nasal immunoglobulin A provides an initial defense against inhaled respiratory pathogens. However, it is not known whether the nasal-associated lymphoid tissues (NALT) are able to mount an effective long-lasting pathogen-specific immune response, nor is it known whether functional differences exist between the organized NALT (O-NALT) and the diffuse NALT lining the nasal passages (D-NALT). Here we show that although both the O-NALT and the D-NALT are capable of producing virus-specific antibody in response to influenza virus infection, the frequency of specific antibody-forming cells in the D-NALT is much greater than the frequency observed in the O-NALT. Furthermore, we show that the D-NALT but not the O-NALT is the site of long-term virus-specific humoral immunity which lasts for the life of the animal. These results indicate that the D-NALT is not only the major effector site of the NALT but also the site of local long-term specific antibody production.The upper respiratory tract is an important site for host defense against invading pathogens, since it is the site at which inhaled antigens first come into contact with the immune system (9). Respiratory viruses such as influenza virus affect primarily the upper and lower respiratory tracts, and viremia does not normally occur. Intranasal immunization can elicit antigenspecific immune responses in both the mucosal and systemic compartments following administration of pathogens and even nonreplicating protein antigens (4,16,17). Furthermore, intranasal immunization is an effective means of evoking not only local immunity in the respiratory tract but also immunity at distal mucosal sites (10, 15).The nasal-associated lymphoid tissues (NALT) in the mouse are composed of a pair of organized lymphoid aggregates (O-NALT) located on the palate at the entrance to the nasopharyngeal duct and the less well organized diffuse lymphoid tissue lining the nasal passages (D-NALT) (9). These nasal tissues appear to be functionally equivalent to the Waldeyer's ring of tonsils and adenoids in the human and are most likely responsible for the local immune responses generated following intranasal immunization in the mouse (14). An indication of the importance of the nasopharyngeal lymphoid tissue in humans is the diminished poliovirus-specific antibody levels in nasal secretions from children following tonsillectomy (11). In humans resistance to infection with a cold-adapted vaccine influenza virus has been correlated with antihemagglutinin (anti-HA) immunoglobulin A (IgA) in nasal washes (3). In the mouse model, following intranasal infection, local antibodyforming cell (AFC) production in the NALT of BALB/c mice parallels detection of influenza virus-specific antibodies in the nasal wash and correlates with virus clearance from the nose (14). Furthermore, nasal IgA has been shown to directly mediate local anti-influenza virus immunity in the mouse model, confirming the importance of IgA in protection against virus infection in the upper respiratory tract (12). Specific AFCs secr...