As the number of HIV-1 sequences has increased in the public database and new tools of immunological bioinformatics have become available, making it possible to better understand at a population level how host immune response drives the evolution of HIV-1 envelope (Env). We analyzed 1100 unique full-length envelope sequences and systematically determined positive selection (PS) sites by QUASI analysis and found that PS sites were widely dispersed across Env. The frequency of Env PS sites appears to be relatively stable over time. Moreover, between 25% and 61% of PS sites are shared between subtypes A, B, C, and D, suggesting that host immune responses target the same regions of Env gene across different clades at the population level. Significant correlations were observed between PS sites and Neutralizing antibody (NAb) response, as well as PS sites and Th epitopes. Furthermore, NAb sites in combination with cytotoxic-T lymphocyte (CTL) epitopes and proteasome cleavage sites were also significantly associated with PS sites, suggesting NAb may be the major force driving the evolution of HIV-1 Env. We also identified regions that are free from PS, but heavily targeted by CTL or NAb, implying that functional constraints may be responsible for the lack of positive selection in these regions. These findings should help researchers to identify epitopes or regions of HIV-1 that may aid in designing vaccines.