Cisplatin is an active palliative chemotherapy agent in advanced upper gastrointestinal cancer, but it is associated with significant non-haematological toxicity. Substitution of cisplatin by carboplatin in combination chemotherapy regimens may reduce these adverse effects. These two phase II studies evaluated the efficacy and toxicity of the combination of mitomycin C (MMC) 7 mg/m2 q 6 weekly, carboplatin area under the concentration-time curve 5 mg/ml/min q 3 weekly and protracted venous infusion 5-fluorouracil (5FU) 300 mg/m2/day (McarboF) in advanced upper gastrointestinal cancer. Between October 1998 and June 2000, 31 patients were enrolled in the studies, 23 patients in the oesophago-gastric study and eight patients in the pancreatic study. Although non-haematological toxicity was modest, both protocols were closed prematurely because of excessive haematological toxicity and frequent treatment delays. The overall incidence of grade 3/4 neutropenia and thrombocytopenia was 39 and 52%, respectively. The McarboF combination showed significant activity with an overall response rate of 52% in advanced oesophago-gastric cancer. Palliative benefit was also evident with improvement in symptoms of pain and weight loss in over 79 and 50% of patients in the oesophago-gastric study and pancreatic study, respectively. Median overall survival times were 10.6 and 6.6 months for patients with oesophago-gastric and pancreatic cancer, respectively. The McarboF regimen showed promising activity in advanced upper gastrointestinal cancer, with modest non-haematological side-effects. This combination merits further evaluation with modification of the dose and schedule of carboplatin and MMC in order to reduce the severity of haematological toxicity.