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Background: Chromogranin A (CgA) is the most important tumour marker for well-differentiated neuroendocrine tumours (NET) and neuron specific enolase (NSE) for poorly differentiated neuroendocrine carcinoma (NEC). This study investigated whether the markers progastrin-releasing peptide (proGRP) and cytokeratin fragments (CKfr) CK8, CK18 and CK19 (MonoTotal) can be of additional value to the histological classification and help predict survival in these patients., Methods: CgA, NSE, proGRP and CKfr were measured in 242 patients with grade 1 NET (G1NET), 38 with grade 2 NET (G2NET), 42 with large cell NEC (LCNEC), 251 with small cell NEC (SCNEC) and in 282 healthy persons. Results were compared with tumour characteristics and survival by means of Receiver Operating Characteristics (ROC) curves and Cox regression analyses., Results: The largest area under the ROC curve was for CgA (0.86, 0.91 and 0.90, respectively) when comparing patients with G1NET, G2NET and LCNEC with healthy persons. ProGRP showed the highest sensitivity (73%) at 95% specificity in patients with SCNEC. In a multivariate survival analysis, only CKfr was associated with survival (P<0.0001) for patients with well-differentiated NET (G1NET and G2NET). For patients with poorly differentiated NEC, both CKfr and NSE were associated with survival (P<0.0001 and P=0.003, respectively)., Conclusion: Within all histological groups a combination of tumour markers proved to be more informative as diagnostic and prognostic marker than each marker alone. In patients with well-differentiated NET and LCNEC we recommend the use of CgA and CKfr, whilst in patients with SCNEC, proGRP and CKfr are preferred., (Copyright © 2011 Elsevier Ltd. All rights reserved.)