There is no ideal tumour marker at present. The clinical application of CYFRA 21-1 is possible once a thorough standardisation process is carried out. Standardisation is achieved by determining the reference range in asymptomatic population, benign and malignant lung diseases, and benign and malignant diseases of other organs. Furthermore, it depends on knowledge of research population characteristics, patient medical histories and individual diagnostic procedure results, the size of research target samples and the clinically defined control groups. The cut-off level of CYFRA 21-1 for non-small cell lung cancer (NSCLC) is 1.72 ng/mL in the Croatian population. It is based on the clinically applicable sensitivity of 78% and specificity of 95% in benign lung diseases. The cut-off value is verified by clinical findings. For clinicians the level of CYFRA 21-1 is an early sign of NSCLC in relation to all the benign lung diseases and all the benign diseases of other organs, of which it was confirmed that they can influence the above level, provided that NSCLC is verified using standard diagnostic methods. The level of CYFRA 21-1 is also influenced by the time of sampling in relation to other diagnostic invasive procedures. The marker is clinically applicable if clinical findings verify it; otherwise, it is useless. This research has involved 343 healthy persons, 474 patients with a benign disease and 4440 patients with a malignant disease, 2453 of whom suffer from NSCLC. The sensitivity of CYFRA 21-1 in NSCLC is 78%, in squamous cell lung cancer (SQC) 84.6%, in adenocarcinomas (AD) 74.3% and in large cell lung cancer (LCC) 75.3%. The level of CYFRA 21-1 differs significantly between healthy persons, benign and malignant diseases (p<10–3). There are differences between the three histological types of NSCLC (p<10–6) and according to T and N (p<10–3). The level of CYFRA 21-1 prompts clinicians to repeat the clinical procedure during diagnosis, and helps to detect the disease earlier and implement treatment in NSCLC. We have achieved high concordance between marker findings and clinical diagnostic.