Inositol-requiring enzyme 1[alpha] (IRE1[alpha])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1 alpha-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) was compromised in IRE1 alpha-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE(2)), was decreased in myeloid cells that lack IRE1 alpha or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human PTGS2 and PTGES genes to enable optimal PGE(2) production. Mice that lack IRE1 alpha-XBP1 in leukocytes, or that were treated with IRE1 alpha inhibitors, demonstrated reduced pain behaviors in PGE(2)-dependent models of pain. Thus. IRE1 alpha-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.