Between 1979 and 1989, families enrolled in the Houston Family Study were prospectively monitored for influenza virus infections. Reinfection with the H3N2 subtype occurred in a number of family members, and 6 pairs of isolates (interval between collection of first and second isolate, 2-5 years) were available for molecular analysis. Changes in the hemagglutinin genes of pairs of viruses isolated from the same individuals were examined to determine the molecular basis for reinfection. The findings of this study indicate that reinfection of an individual by viruses of the same subtype may occur within a relatively short period of time when the paired strains have genetically distinct hemagglutinin genes in which amino acid changes are present in the defined antigenic sites.