A case of recurrent pancreatic cancer effectively responded to S-1 and irinotecan combined with third-line chemotherapy (IRIS) with PSK. The patient was a 75-year-old female. In October 2007, a pancreatoduodenectomy was performed, followed with 6 courses of systemic adjuvant chemotherapy of gemcitabine (GEM). Three months after finishing the adjuvant chemotherapy, a recurrence of para-aortic lymph node metastasis was confirmed. We resumed the second-line chemotherapy of S-1/GEM (GS) with PSK. GS therapy was continued for about 3 years, until the recurrent lesion was found to have increased after 30 courses. Nevertheless, we continued up to 39 courses. In November 2011, we started third-line chemotherapy using S-1/irinotecan (IRIS) with PSK. The regimen was S-1 of 80 mg/body/day, continuously administered for day 1-14th, followed by a discontinuation for 2 weeks. CPT-11 100 mg/body/day was administered on day 1 and 15th; and PSK of 3 g/ body/day was continued, until it resulted in increased recurrent lesions. After the end of 4 courses, recurrent lesions started to respond partially. Currently, the patient is being treated as an outpatient. This case indicates that IRIS (S-1/CPT-11) is an effective therapy when pancreatic cancer fails to respond to GS therapy.