Very early detection of HIV infection could help decrease the spread of HIV, improve safety of the blood supply, and permit earlier treatment. Early detection was reported when native gp41 antigen was used to detect antibodies that occurred 2-6 weeks earlier than detection of antibodies to denatured antigens by the current EIA or WB tests or detection by the HIV RNA test. We hypothesized that early antibodies to native gp41/160 could be detected, not only by the reported live-cell immunofluorescence (IFA) but also by a neutralization test, since virions as well as HIV-infected cells contain native gp41/160. To test this hypothesis, we did an initial test of concept study to compare the neutralization test with other tests, using sera from 12 high-risk patients. The neutralization test reproducibly detected early antibodies (characterized) in the sera of 10 of 12 (83%) high-risk subjects. Importantly, the EIA and WB tests that use denatured antigens missed the early diagnosis in 12 of the 13 subjects (92%). The findings support the concept that native HIV antigens can detect polyclonal HIV neutralizing antibodies and live-cell IFA antibodies earlier than currently available tests that use denatured antigens.