The study presents data comparing the relatively new tumor metabolic marker Tumor-M2-PK with the established markers CEA, CA 19-9 and CA 72-4 in the diagnosis of gastrointestinal cancers. In this prospective study histologically confirmed n = 250 colorectal, n = 122 gastric, n = 86 oesophageal and n = 24 pancreatic cancer patients were investigated and compared with n = 76 control persons without any malignant disease. Tumor M2-PK was measured in plasma by an ELISA. CEA, CA 19-9 and CA 72-4 were determined in sera by an autoanalyser. Significantly elevated tumor marker concentrations were detected in the tumor patients suffering from colorectal, gastric, oesophageal and pancreatic cancers. In patients with colorectal cancer Tumor M2-PK was significantly frequently elevated (47.8%), followed by CEA (33.6%) or CA19-9 (30.4%). In gastric cancers, the sensitivity of Tumor M2-PK (57.0%) and CA 72-4 (60.7%) were comparable and higher than CA19-9 (45.5%) or CEA (23.8%). In oesophageal cancers, Tumor M2-PK was most frequently elevated (55.8%) followed by CA 72-4 (53.5%), CA 19-9 (27.9%) and CEA (14.5%). In pancreatic cancer patients, the sensitivities were CA 19-9 (87.5%), Tumor M2-PK (72.9%) and CEA (33.3%). The discrimination power (demonstrated by the AUC) of Tumor M2-PK was superior in colorectal, gastric and oesophageal cancers without distant metastasis. Also CA 72-4 was superior to CA 19-9 or CEA in detection of gastric or oesophageal cancer patients. CEA bore no relevant information for the detection of localised cancers. The present data indicate that Tumor M2-PK could be a valuable tumor marker for the detection of gastrointestinal cancers.