The recognition of an antigenic relationship between the haemagglutinins of A/Equi-2 and A2/Hong Kong/68 viruses led to experimental studies in man and horses with these virus types.Human volunteers were inoculated with A/Equi-2/Miami/63 virus and virus shedding ensued in all subjects. The most common clinical response was a febrile illness indistinguishable from naturally occurring human influenza. After administration of A2/Hong Kong/68 virus to 10 ponies there was virus shedding from 9 and a febrile response in 6.When the human subjects previously inoculated with equine virus were challenged with A2/Hong Kong/68 virus, the frequency of illness and the extent of virus shedding were lower than was observed among control individuals. This immunity was found to be related to the level of heterologous serum antibody to the human virus which developed after equine virus infection. Challenge with A/Equi-2/Miami/63 virus of ponies previously inoculated with A2/Hong Kong/68 virus, in the absence of any measurable levels of heterologous antibody to the human strain, resulted in less shedding of virus among these than occurred in control animals.