The diagnostic value of Cyfra 21-1 in non-small lung cancer (NSCLC) has been established, but few studies have focused on its prognostic value. The aim of this study was to compare that of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, CA 125, neuron-specific enolase and squamous cell carcinoma antigen. 116 patients with unresectable (n = 88) or resectable (n = 28) NSCLC were prospectively monitored from diagnosis, for a median of 14.4 months. All patients underwent tumour-marker determinations before treatment, then every 3 months. Their diagnostic value was studied using ROC (receiver operating characteristic) curves, based on control measure in 23 patients with benign lung diseases. The prognostic analysis was based on overall survival as the main endpoint. The diagnostic value of Cyfra 21-1 was confirmed, with a sensitivity of 54% and a specificity of 96% at a cut-off value of 3.3 ng/ml. At diagnosis, in the 88 non-surgical NSCLC, besides the presence of metastases (P = 0.017), Cyfra 21-1 (P = 0.017) and CA 125 (P = 0.03) were related to outcome. Elevated levels of Cyfra 21-1 at any time during the disease course was selected by multivariate analysis as additional predictors of poor survival.