Expression of the intrinsic cellular caspase inhibitor XIAP is regulated primarily at the level of protein synthesis. The 5' untranslated region harbours an Internal Ribosome Entry Site (IRES) motif that supports cap-independent translation of XIAP mRNA during conditions of cellular stress. In this study, we show that the RNA-binding protein HuR, which is known to orchestrate an antiapoptotic cellular program, stimulates translation of XIAP mRNA through XIAP IRES. We further show that HuR binds to XIAP IRES in vitro and in vivo, and stimulates recruitment of the XIAP mRNA into polysomes. Importantly, protection from the apoptosis-inducing agent etoposide by overexpression of HuR requires the presence of XIAP, suggesting that HuR-mediated cytoprotection is partially executed through enhanced XIAP translation. Our data suggest that XIAP belongs to the HuR-regulated RNA operon of antiapoptotic genes, which, along with Bcl-2, Mcl-1 and ProTα, contributes to the regulation of cell survival.