Sequential virus isolates from eight cynomolgus monkeys experimentally infected with SIVsm were studied for susceptibility to neutralization by autologous antibodies. The biological and antigenic characteristics of sequential reisolates differed both from the inoculum virus and from each other. Five monkeys developed neutralizing antibodies to the inoculum virus and the 12-day reisolate at 4 months postinfection, while the remaining three monkeys produced very little, if any, neutralizing antibodies. Strikingly, the two long survivor monkeys developed neutralizing antibody response to a second or third autologous reisolate and to 12 reisolates obtained from other monkeys. Thus the neutralizing antibody response of the long survivor monkeys showed a relatively broad specificity, whereas the neutralizing antibody response of the monkeys with early disease, if at all present, was specific for the infecting strain only and lost over time. Our results show that the pattern of virus neutralization in SIVsm-infected monkeys is similar to human immunodeficiency virus type 1-infected humans. In both cases, variant viruses resistant to neutralization by autologous sera emerge during the entire course of infection. In addition, the ability to produce autologous neutralizing antibodies to sequential virus reisolates appeared to correlate with the degree of immunodeficiency in the host.