Intraperitoneal immunization of mice with live influenza virus was shown to induce helper T (T(H)) cells with specificity for the hemagglutinin (HA). The interaction of virus-primed T(H) cells with purified HA was studied independently of B cell reactivity to the same antigen by using the generation of nonspecific help as an index of activation of HA-specific T(H) cells. T(H) cells from mice primed with any of the H3 viruses A/Aichi/68 x A/Bel/42 (H3N1), A/Memphis/102/72 x A/Bel/42 (H3N1) or A/Port Chalmers/73 (H3N2) were strongly cross-reactive towards HA of other strains within the 3 subtype. In addition, several examples of cross-reactivity towards HA of a different subtype were observed, usually of a lower magnitude. T(H) cells from mice primed to any of the H3 viruses above or to A/Bel/42 (HlNl) virus cross-reacted with the HA of A/Japan/305/57 (H2); furthermore, priming with A/Bel/42 or with A/Jap/305/57 x A/Bel/42 (H2N1) virus yielded T(H) cells that cross-reacted with certain of the H3 HA preparations. The cross-reactivity observed between subtypes was not due to the common chicken host carbohydrate component of HA, since no response to the purified type A HA preparations was obtained with T cells from mice primed with egg-grown influenza B/Hong-Kong/8/73 virus. The results indicate that HA of different subtypes may share cross-reactive antigenic determinants recognized by T(H) cells. Within a subtype, HA are highly cross-reactive with respect to T(H) cell recognition.