Suppression of apoptosis has been proposed as a mechanism involved in the transforming action of human T-cell leukemia/lymphotropic virus type-1 (HTLV-1). However, there is evidence that HTLV-1 and its protein Tax also induce apoptosis. To resolve this apparent paradox, apoptosis was monitored in primary cultures of peripheral blood lymphocytes (PBLs) from healthy donors, following HTLV-1 infection in vitro. High levels of apoptosis in HTLV-1 infected cultures during the first weeks after infection were detected. Apoptosis was not related to the presence of uninfected cells, as revealed by a fluorescence in situ hybridization assay. Successively, a progressive decrease in apoptosis in infected cultures going towards immortalization, was observed. When IL-2 in the medium was replaced by IL-4, allowing the cells to be efficiently infected by HTLV-1 but not immortalized, apoptosis levels tended to increase, instead of decreasing, with the ongoing time. The caspase cascade was remarkably activated in PBLs recently infected in vitro by HTLV-1, but apoptosis was only partly reduced by caspase inhibitors. Even if spontaneous apoptosis was relatively low in long-term cultures of PBLs immortalized by HTLV-1 in vitro, Fas death-receptor expression and function were well conserved. These observations provide a new rationale for explaining the dual effect of HTLV-1 in controlling apoptosis. © 2004 Wiley-Liss, Inc.