We evaluated the efficacy of IORT for unresectable Stage IVb (Japan Pancreas Society classification) pancreatic cancer. Twelve patients were treated with IORT, 17 with external beam radiotherapy (ERT) and 17 with chemotherapy (CHT, 8 patients doxorubicin-based, 7 patients 5-FU-based). Survival, hospital-free survival and pain relief were compared among the three groups. In the IORT group, 7 patients underwent bypass surgery, 3 celiac plexus blockade, 3 ERT, 2 hyperthermia and 2 CHT. In the ERT group, 1 patient underwent bypass surgery, 7 hyperthermia and 14 CHT. Distant metastases were more frequently found in the CHT group than in the IORT group. Median survival and median hospital-free survival were 208 and 79 days in the IORT group, 125 and 32 days in the ERT group and 76 and 9 days in the CHT group, respectively. Pain relief was obtained in 45% (5/11) of symptomatic patients after IORT and in 27% (4/15) after ERT. No patient (0/13) in the CHT group experienced pain relief. In conclusion, our experience suggests that IORT can reduce pain and improve QOL in patients with unresectable pancreatic cancer.