In Drosophila, Eiger, a tumor necrosis factor α (TNFα) superfamily ligand, induces cell death by activating the c‐Jun N‐terminal kinase (JNK) pathway. Here, we report that overexpression of Plenty of SH3s (POSH) suppresses Eiger‐induced cell death and produces highly deformed tissues. These results imply that high levels of POSH protect tissues from cell death. In humans, rheumatoid arthritis synovial fibroblasts (RASF) are generally resistant to apoptosis. We show that POSH is expressed at relatively high levels in RASF, and its reduction by RNAi sensitizes these cells to Fas‐mediated apoptosis. Thus, we demonstrate that POSH promotes cell survival in Drosophila and in human RASF.