BACKGROUND: Although perioperative hypothermia was found to be associated with gastrointestinal anastomotic leakage in preclinical studies, its association with postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy was never evaluated. We investigated the association between intraoperative hypothermia and clinically relevant (CR)-POPF following pancreaticoduodenectomy. METHODS: We retrospectively reviewed 2163 consecutive patients who underwent pancreaticoduodenectomy during 2007-2019. Based on intraoperative time-weighted average core temperature, patients were grouped into normothermia (36.0-37.5°C), mild hypothermia (35.0-<36.0°C), and severe hypothermia (<35°C). We conducted multivariable logistic regression analysis for CR-POPF, a propensity score analysis using inverse probability of treatment weighting (IPTW) to adjust the baseline differences between the three groups, followed by multivariable logistic regression with IPTW for CR-POPF. RESULTS: Among the 2008 patients analysed, 1118 (55.7%) and 120 (6.0%) had mild and severe hypothermia, respectively, and 14.2% overall incidence of CR-POPF. Severe intraoperative hypothermia was significantly associated with CR-POPF before and after IPTW (before: odds ratio [OR] 1.79, 95% confidence interval [CI]: 1.03-3.09, P = .038; after: OR 2.48, 95% CI: 1.28-4.81, P = .007); however, mild hypothermia had no significant associations. CONCLUSION: Severe intraoperative hypothermia is significantly associated with the occurrence of CR-POPF following pancreaticoduodenectomy, suggesting that hypothermia is deleterious on pancreaticojejunal anastomotic healing.