An influenza A virus isolated from seals replicated in the trachea and nasopharynx of squirrel monkeys to a level similar to virulent human virus. This virus initiated a systemic infection involving the spleen, liver, and muscle. Transfer of the six internal genes of the avian A/Mallard/78 (H2N2) virus (i.e., genes that code for nonsurface viral proteins) to three human influenza viruses (H1N1 or H3N2) reproducibly attenuated the resulting reassortant viruses for monkeys and hamsters. When tested in monkeys the human A/Wash/80 X avian A/Mall/78 reassortant was satisfactorily attenuated, not transmissible, stable as regards phenotype, and immunogenic. Immunogenicity was demonstrated by the induction of resistance to challenge with wild-type virulent human virus. These studies form the basis for evaluation of these promising reassortants in man. The NP and M genes of the avian A/Mallard/78 (H2N2) virus donor appear to play the greatest role in conferring attenuation on avian-human influenza virus reassortants. The 6 internal genes of 2 other avian influenza viruses [A/Mallard/Alberta/78 (H1N1) and A/Pintail/Alberta/79 (H7N8)] that grow poorly in monkeys confer this restriction upon human-avian influenza virus reassortants into which they are transferred. With each of 3 avian influenza viruses tested thus far one or more internal genes constitute the basis for restriction of replication in primate respiratory tissue.