We analyzed the env genes of cytopathic and noncytopathic biological clones derived from two HIV-1-infected children with discordant clinical courses. Chimeric viruses were constructed by switching env regions from V2 through V3 of the biological clones with the corresponding region from the molecular clone NL4-3. These HIV-1 chimeric viruses exhibited similar replication kinetics as well as syncytium-inducing abilities. The chimeric virus containing the env region of noncytopathic biological clone, GC6 8-4, was noncytopathic in an in vitro cell-killing assay, while the chimeric virus containing the env region of cytopathic biological clone, HC4, was cytopathic in the in vitro cell-killing assay. These studies suggest the presence of a cytopathicity determinant that maps to the envelope sequences contained within the downstream region of V2 and within the V3 region (nucleotide position 6822 to nucleotide position 7250, based on NL4-3 sequence).