We evaluated the antigenic stability of viruses within the H1N1 subtype, using 307 isolates spanning four winter seasons. The isolates from each seasonal period appeared relatively homogenous in hemagglutination inhibition tests employing ferret antisera. However, a panel of seven monoclonal antibodies to A/USSR/90/77 detected extensive micro-heterogeneity. Antigenic variation occurred in the hemagglutinin antigen within a few weeks after the initial appearance of A/USSR/90/77-like strains in 1977-78 season as evidenced by low reactivity to one or several of the monoclonal antibodies. By the end of the season, few of the isolates reacted with the complete panel. Antigenic heterogeneity of the hemagglutinin was detected among H1N1 viruses throughout each epidemic interval. Some of the antigenic changes detected by monoclonal antibodies appeared on isolates in succeeding years, but others were restricted to a few strains isolated during a given year. The cumulative nature of some of these antigenic changes was indicated by the observation that 20 (19%) of 107 isolates examined in the fourth season failed to react with five of the monoclonal antibodies. Strains similar to most reference variants from around the world circulated in the Houston community.