Serologic diagnosis of influenza is an important but imperfect tool. During an outbreak of natural H1N1 A/USSR/77 infection, volunteers who received either amantadine, rimantadine, or placebo were tested to determine serologic response to infection by four different antibody techniques. Hemagglutination inhibition (HAI) and complement fixation (CF) were least sensitive, detecting only about half of the virus-positive subjects, whereas neutralization detected 81% and enzyme-linked immune peroxidase (ELISA) detected 95%. Failure to detect significant antibody response was associated with a higher titer of antibody in acute serum specimens and with a history of receipt of A/New Jersey/76 Hsw1N1 vaccine. Although antibody response measured by ELISA was of lower magnitude in vaccinees, it still was sufficient to be diagnostic. Thus, in situations where there is no access to viral isolation facilities, ELISA antibody techniques appear to be an excellent measure of assessing the rate of influenza infection.