The effect of influenza virus infection on the expression of major histocompatibility complex (MHC) antigens was investigated. Infection with influenza virus resulted in an increase of the binding of anti-MHC class I and class II antibodies to resting T cells. The binding of anti-MHC class II antibodies to activated T cells was increased approximately threefold. The binding of anti-MHC class I and class II antibodies to Epstein-Barr virus-transformed B cells appeared unaffected after influenza virus infection. Recombinant human interferon-alpha and/or -gamma added to T cells did not enhance the binding of anti-MHC antibodies. Biochemical analysis revealed no increase in the amount of class I and class II antigens as a consequence of viral infection, but a marked decrease in sialic acid content was found, most probably caused by the viral neuraminidase. Pulse-chase experiments suggest that the viral neuraminidase can catalyze the removal of sialic acids both en route to and at the cell surface. The absence of sialic acid residues can explain the increased binding of anti-MHC antibodies, because neuraminidase (clostridium perfringens) treatment of T and Epstein-Barr virus-transformed B cells resulted in a shift in both isoelectric point and antibody binding similar to that observed after influenza virus infection.