Members of the caspase family are essential executors of apoptosis. Caspase‐2 has two messenger RNAs generated by alternative splicing, which encode caspase‐2L and caspase‐2S. Although caspase‐2L induces apoptosis, caspase‐2S also has the ability to antagonize cell death. Experiments in caspase‐2‐deficient mice showed that caspase‐2 functions to delay cell death in some neuronal populations, suggesting that caspase‐2S dominantly acts for cell survival in the brain. However, the mechanism of caspase‐2S‐mediated anti‐apoptotic effect is still unclear. Here, we isolated a protein that interacts with caspase‐2S, designated as Ich‐1S (caspase‐2S)‐binding protein (ISBP), by yeast two‐hybrid screening using full‐length caspase‐2S cDNA as a bait. ISBP is identical to the recently isolated calcium and integrin‐binding protein, and a small molecule calcium‐binding protein with two EF‐hand motifs of its C‐terminus. In vitro transcribed and translated ISBP interacts specifically with glutathione‐S‐transferase‐fused caspase‐2S. Moreover, the interaction between ISBP and caspase‐2S was observed in cultured cells. Northern blot analysis indicated that ISBP may be a ubiquitous protein. Interestingly, ISBP can partially inhibit the processing of pro‐caspase‐2L induced by anti‐Fas antibody‐treated Jurkat cytosolic lysates. These results suggested that ISBP may be the mediator for the survival function of caspase‐2S.