A longitudinal cohort study was conducted to define the prevalence and temporal pattern of antibody response to the HIV-2 virion-associated proteins p26gag and Vpx. One hundred and forty-one asymptomatic HIV-2-infected women were enrolled, and followed for up to 11 years. Eighty-one percent of the subjects had antibodies to p26, and 51% to Vpx; response to these two antigens was not correlated. The response to both proteins was determined early in infection, and remained stable over time. The absence of antibodies to p26 was a highly significant predictor of CDC category IV HIV-related disease (p < 0.01) in both univariate and multivariate analysis. Antibody response to Vpx alone was not associated with disease progression. However, those individuals lacking anti-p26 antibodies, and with anti-Vpx antibodies, were six times more likely to be classified as CDC category IV by the end of the study (p < 0.01). This represents the first identification of virus-specific serological markers for HIV-2-related disease progression.