Neutralizing activity against primary human immunodeficiency virus type 1 (HIV-1) isolates from 17 persons who were long-term disease nonprogressors (LTNPs) and 13 persons who were fast progressors (FPs) was compared. Sera from LTNPs showed higher neutralizing activity both in titer and in host spectrum than did sera from FPs. However, LTNP sera had limited neutralizing activity against HIV-1 subtypes from different geographic areas. Sera collected 6 years earlier from both groups had limited neutralizing activity, indicating that early responses are not predictive for disease progression. LTNPs had very low virus loads, as reflected by only one positive isolation, which was an MT-2-negative phenotype. Virus was isolated from all FPs, and the isolates showed a phenotype switch from MT-2 negative to MT-2 positive. Development of high-titer, broadly cross-reactive neutralizing antibodies is associated with control of virus replication and low virus load in HIV-1-infected LTNPs.