Influenza virus stimulation of human lymphocytes induced high levels of immune interferon in lymphocyte cultures. The lymphocytes of normal adults produced approximately 1,000 U/10(6) cells, which was in large part gamma interferon. The lymphocytes of individuals recently vaccinated yielded very high levels (10-50,000 U/10(6) cells) of interferon. The interferon was pH 2 labile, and was not neutralized by antisera to alpha or beta interferon. It did not bind to a monoclonal antibody to alpha interferon, and after partial purification it had characteristics identical to human gamma interferon induced by phytohemagglutinin. The highest yields were produced by treatment of stimulator cells with live virus. Stimulation by whole inactivated virus resulted in lower levels of interferon, and purified hemagglutinin did not induce interferon. The antigen responsible for stimulating the lymphocyte response and interferon induction is a cross-reactive determinant present on all human and non-human influenza viruses tested.