Participants in the Houston Family Study were observed during a period of two mixed outbreaks due to two subtypes of influenza A virus: H3N2 and H1N1 (1977-1981). Virus specimens, serum samples, and clinical records were obtained to identify and characterize infections. In 1977-1978, 40% of 238 persons in 59 families were infected by influenza A virus (H3N2), 11% by influenza A virus (H1N1), and 4% by both. In 1980-1981, for 319 persons in 79 families, the corresponding rates were 27%, 20%, and 5%. Interference between subtypes was not detected. Both subtypes were isolated from six children (range of intervals between isolations, six to 55 days), and five of the six were ill with both infections. Nineteen persons had two infections with one or both detected serologically; illnesses were associated with 77% of isolates and up to 56% of seroconversions in these persons. Infection of the same individual with two subtypes in the same season is a newly observed phenomenon that may affect the future epidemiology of influenza A virus as well as preventive measures.