Mutations in pyrin cause the autoinflammatory disorder familial Mediterranean fever (FMF), a syndrome characterized by sporadic and unpredictable attacks of fever and localized severe pain. Currently, it is not clear how attacks are triggered, nor why they spontaneously resolve after 2 or 3 days. In fact, the cellular function of the pyrin protein and the molecular underpinnings of its malfunction in FMF have so far eluded clear definition. The identification of pyrin‐interacting proteins has the potential to increase our understanding of the cellular networks in which pyrin functions. Previous reports have established that pyrin interacts with the apoptotic protein ASC, the cytoskeletal adaptor protein PSTPIP1, the inflammatory caspase, Caspase‐1 and certain forms of the cytosolic anchoring protein 14‐3‐3. Here, we report that pyrin also interacts with Siva, a pro‐apoptotic protein first identified for its interaction with the cytosolic tail of CD27, a TNF family receptor. The interaction between pyrin and Siva involves the C‐terminal B30.2/rfp/SRPY domain of pyrin and exon 1 of Siva. We show that Siva and pyrin are indeed co‐expressed in human neutrophils, monocytes, and synovial cells. Furthermore, using a novel protein/protein interaction assay, we demonstrate that pyrin can recruit Siva to ASC specks, establishing a potential platform for intersection of ASC and Siva function. Finally, we show that pyrin modulates the apoptotic response to oxidative stress mediated by Siva. Thus, the Siva–pyrin interaction may be a potential target for future therapeutic strategies. J. Cell. Physiol. 216: 595–602, 2008, © 2008 Wiley‐Liss, Inc.