Background: In a phase III trial, the addition of erlotinib to gemcitabine improved the survival in advanced pancreatic cancer compared with gemcitabine alone. In addition, gemcitabine in combination with oxaliplatin was superior to gemcitabine alone in terms of the progression-free survival and response rate in one phase III trial. Therefore, this study evaluated the safety and activity of erlotinib with gemcitabine and oxaliplatin combination chemotherapy given as first-line therapy for locally advanced unresectable or metastatic pancreatic cancer. Methods: Patients with chemotherapy-naïve, histologically confirmed, unresectable or metastatic pancreatic cancer were given GEMOX-T (oral erlotinib 100 mg daily, gemcitabine 1000 mg/m² iv, and oxaliplatin 50 mg/m² iv on days 1 and 8) every 3 weeks. The primary endpoint was the response rate. Results: An enrollment of 32 patients was planned, and 33 patients are registered. The patients’ median age was 58 (range 31–82) years. 29 patients were evaluable and 13 patients (45%) had partial responses. The disease control rate was 86.2%. 148 chemotherapy cycles were delivered (median, 4 ; range, 1-18). The median progression free survival was 4.8 months (95%CI: 4.1-5.5) and the median overall survival was 8.4 months (95%CI: 7.0-9.8). Generally, GEMOX-T was well tolerated. The major grade 3/4 hematological toxicities were neutropenia (20%) and anemia (17%), which were manageable. The main non-hematological toxicities were nausea (29%), anorexia (29%), rash (27%), fatigue (25%), and diarrhea (24%); these were mainly grade 1/2 (95, 86, 100, 97, and 91%, respectively). There was no treatment-related mortality. The relative dose intensities of gemcitabine, oxaliplatin, and erlotinib were 97, 97, and 100% of the planned doses, respectively. Conclusions: GEMOX-T appears to be active as first-line chemotherapy for unresectable or metastatic pancreatic cancer, and the safety profiles are acceptable. Also, the high response rates of GEMOX-T may allow initially unresectable patients to undergo resection. Clinical trial information: NCT01505413.