The most commonly used treatment in the palliative first-line therapy of metastatic pancreatic adenocarcinoma is the Gemcitabine (Gem) monotherapy, while several combination therapies are currently being tested in clinical trials. With regard to pancreatic cancer, a palliative second-line therapy has not been established, yet. The four patients presented in this paper received a palliative second-line therapy with Oxaliplatin (L-OHP), Gem and high-dose 5-Fluorouracil (5-FU) as a 24-h infusion after a first-line therapy with Gem and weekly high-dose 5-FU as a 24-h infusion. During second-line therapy, four patients received 67 chemotherapy applications, which were well tolerated. As severe symptom of toxicity, thrombocytopenia (CTC toxicity grade 4) was observed in one patient. As a result of second-line therapy, stable disease (SD) with a significant decrease of CA 19-9 was achieved in three patients and partial remission (PR) in one patient. After palliative first- and second-line treatment the survival time of the patients was 9, 9,15 and 20 months. Currently, a multicentre phase 1 study has been started aiming at an optimisation of the three-drug combination dosage.