In two mutant clones (L and H) of A/NJ/11/76 (Hsw 1N1) influenza viruses which differ slightly antigenically and markedly in replication characteristics in chicken embryos and Madin Darby canine kidney cells, these pleiotropic differences are mediated by mutation in the hemagglutinin gene (E. D. Kilbourne, Proc. Natl. Acad. Sci. U.S.A. 75:6258--6262, 1978). Experimental infection of swine with either the mutant L and H clones or recombinant viruses differing genetically only with respect to the presence of L or H hemagglutinin demonstrated greater infectivity for the natural host of viruses bearing the L hemagglutinin. Introduction of the L but not the H hemagglutinin gene into the human influenza virus A/PR/8/34 rendered it infective for swine. Both L and H variants were isolated from pigs naturally infected with contemporary swine influenza viruses when selective conditions for the suppression of the more prevalent L mutant were employed. The L and H mutants of swine influenza virus are yet another example of viral dimorphism in nature and probably are not mere artifacts of laboratory selection. In any event, the frequent apparent allelic appearance of the two forms suggests frequent mutation and/or reversion involving a point mutation in the hemagglutinin gene. The present studies demonstrate the importance of a single gene in the pathogenesis of an influenza viral infection in its natural host.