The E3 ubiquitin ligase synoviolin (SYVN1) functions as an anti‐apoptotic factor that is responsible for the outgrowth of synovial cells during the development of rheumatoid arthritis. The molecular mechanisms underlying SYVN1 regulation of cell death are largely unknown. Here, we report that elevated SYVN1 expression correlates with decreased levels of the protein inositol‐requiring enzyme 1 (IRE1)—a pro‐apoptotic factor in the endoplasmic reticulum (ER)‐stress‐induced apoptosis pathway—in synovial fibroblasts from mice with collagen‐induced arthritis (CIA). SYVN1 interacts with and catalyses IRE1 ubiquitination and consequently promotes IRE1 degradation. Suppression of SYVN1 expression in synovial fibroblasts from CIA mice restores IRE1 protein expression and reverses the resistance of ER‐stress‐induced apoptosis of CIA synovial fibroblasts. These results show that SYVN1 causes the overgrowth of synovial cells by degrading IRE1, and therefore antagonizes ER‐stress‐induced cell death.