Previously, we reported that cells of the human T-cell lymphotropic virus type I (HTLV-I)-transformed lines MT-2 and MT-4 were extensively killed by infection with AIDS retrovirus HTLV-III. We have investigated this phenomenon more systematically using light and electron microscopy as well as immunofluorescence. The cell lines used in the present studies included 14 of those carrying not only human HTLV-I but also related simian agents and 6 HTLV-I-negative T- and B-cell lines. The results showed that the cytocidal effects occurred in the HTLV-I-transformed cell lines exclusively and were not present in further subcultures. In these cell lines the cytotoxic response was closely correlated with the induction of HTLV-III antigens after virus infection. However, cells of 6 HTLV-I-free lines were not killed to a marked extent by HTLV-III and were passaged as continuous producers of AIDS virus. Only 2 cell lines were resistant to the cytocidal effect of HTLV-III among 14 HTLV-I carrying cell lines. They were also resistant to the replication of infected HTLV-III. This AIDS virus-specific cytotoxic effect observed in HTLV-I-transformed cell lines did not appear to be associated with gene expression of the gag and pXs region of HTLV-I genomes. This result may indicate that HTLV-III specifically interferes with some steps of HTLV-I transformation.