Introduction. The incidence of esophageal cancer is rising worldwide; however, this disease is often diagnosed at advanced stages, which leads to poor prognosis and low 5-year survival. Thus, the search for prognostic predictors for both adenocarcinoma and squamous cell carcinoma of the esophagus is necessary. The aim of our study was to evaluate the immunohistochemical profile of markers that define differentiation and biological behavior of squamous cell carcinoma and adenocarcinoma of the esophagus. Materials and methods. The research included 100 patients with morphologically proven esophageal cancer. Biopsy specimens of esophageal mucosa obtained during EGDS were fixed in 10% buffered formalin and stained with hematoxylin and eosin and combined PAS/Alcian blue. We performed immunohistochemical evaluation with the following markers: p53, p16, Ki-67, CK5/6, p63, MUC5AC, MUC6, and MUC2. Results. Forty patients had squamous cell carcinoma, 53 adenocarcinoma, and 7 anaplastic cancer. High p53 expression was shown in 45.83% of patients with squamous cell cancer and in 50% of patients with adenocarcinoma (no statistical difference: p>0.05, Fisher’s test). High p16 IHC level prevailed in adenocar-cinoma (54% vs. 8.33%, p<0.05, Fisher’s test). In both cancer types, high p16 IHC level was more common in patients with low p53 IHC level. High Ki-67 more often coincided with high p53 IHC levels in both histological types of esophageal cancer (p<0.01, Fisher’s test). Conclusion. Immunohistochemical evaluation with p53, p16, and Ki-67 in adenocarcinoma and squamous cell carcinoma provides valuable information for disease prognosis. © 2025.