Weanling ferrets were inoculated intranasally with either wild-type or receptor-variant clones of influenza A/Memphis/102/72 to determine if changes in receptor specificity influence virulence of influenza virus infection. Over the 5 days after inoculation, receptor-variant inoculated ferrets had a lower mean elevation in body temperature, greater weight gain and less sneezing than the wild-type group. Influenza virus was recovered from the lungs of fewer receptor-variant infected ferrets (5/12 vs 11/12) and in lower titers than in wild-type infected ferrets at 5 days after inoculation. The viruses recovered from lung homogenates retained the same receptor specificity as the inoculum. Serum hemagglutination inhibition titers for the two groups were similar. These findings suggest that the receptor-variant clone is less virulent but elicits a similar immunogenic response compared with the wild-type clone.