Sera from persons of four age groups (1 to 2 years, 2 to 5 years, 20 to 30 years, and 65 to 85 years) were analyzed for hemagglutination inhibition (HI) activity for influenza C virus. Significant HI activity was found in 66% of the 237 sera tested, and titers ranged from 8 to 512. In the yoiung adult group, 96% had antibody and the highest mean titer (74.7) of any age group. Positive sera were far less common in young children (36 to 47%), and relatively low titers (18.3) were common among adults over 65. The high percentage of sera with antibody to influenza C virus suggests that infections with this virus occur at a rate greater than previously recognized. The high percentage of young adults with elevated levels of HI antibody suggested either that an immune response to influenza C infections is common or that the observed HI activity might be attributable, in part at least, to nonspecific inhibitors in the sera. We showed both directly and indirectly that most if not all the inhibitory activity in the human sera we examined was due to specific antibody, mostly immunoglobulin G. This conclusion is based on the finding that the single serum protein fraction with HI activity was found to have a molecular weight equivalent to that of 7S antibody (150,000) and that the HI activity was removed by absorption to staphyloccal protein A. Moreover, immunoglobulin from only HI-positive sera bound specifically to cells infected with influenza C virus, as shown by inhibition of hemadsorption and immunofluorescence. These findings were supported by similar results obtained with chicken antisera to C virus.