The aim: to find the optimal combination of immunohistochemical markers for differential diagnosis and prognosis of small cell lung cancer in small biopsy samples. Materials and methods. The tumor specimens were divided into 3 groups: 1) 25 biopsy samples of small cell lung cancer before treatment; 2) 25 samples of small cell lung cancer procured from autopsies of patients, who underwent chemotherapy; 3) 15 biopsy samples of other lung tumors histologically similar to SCLC. All tumor samples were formalin fixed and paraffin embedded (FFPE). Immunohistochemical study performed with 5 primary antibodies: CD56, p16ink4A, TTF-1, CD117, Ki-67. Results. TTF-1 was positive in all small cell lung cancer, lung adenocarcinomas and atypical carcinoids. Expression of CD56 was positive in 100 % of tumors from 1st group and 92 % of these tumors had more than 25 % of positive tumor cells. Expression of p16ink4A was significantly higher in 1st group than in the 3rd one (р<0,001). The stepwise logistic regression was used for finding the best markers for differential diagnosis of small cell lung cancer in small biopsy samples. The next combination of markers was chosen: TTF-1/CD56 (score 2–4)/p16 ink4A/CD117 (sensitivity – 80 %; specificity – 86.67 %; р<0,001) where “score 2–4” means expression of CD56 more than in 25 % tumor cells. Expression of Ki-67 was higher in the 2nd group compared with the 1st one (р<0,001). Conclusion. Evaluation of p16 expression can be used as additional marker for differential diagnosis of small cell lung cancer. The following combination of markers: TTF-1/CD56 (score2-4)/p16 ink4A/CD117 could be useful in diagnosis of small cell lung cancer in small biopsy samples and in the choice of targeted chemotherapy. The further study in paired tumor samples of small cell lung cancer before and after chemotherapy is required to prove the significance of changes in expression of Ki-67, CD56, CD117 and p16ink4A