Lifeguard (LFG), an anti-apoptotic protein with high expression rates in breast cancer cells, has been identified as a molecule that inhibits death mediated by Fas. The molecular function of LFG and its regulation in the carcinogenesis of human breast and sarcoma cells, however, remains to be elucidated. In the present study, we investigated the ability of LFG expression to inhibit apoptosis induced by the alkyl-phospholipid perifosine. Results showed that LFG was able to be downregulated in selected sarcoma and breast cancer cell lines characterized by high endogenous LFG expression. A decreased LFG expression led to enhanced sensitivity to treatment with an agonistic Fas antibody or treatment with perifosine. Taken together, our findings indicate the role of LFG as an anti-apoptotic protein and provide further evidence of the potential of LFG as a target for the development of novel therapeutic strategies.