Background: Currently, relevant issues include the study of the role of immunohistochemical markers in patients with diffuse large B-cell lymphoma (DLBCL) with extranodal involvement to predict the outcomes of the conducted therapy. Methods: A retrospective study included 81 patients with diffuse large B-cell lymphoma (DLBCL) involving the liver and spleen with extranodal manifestations, who underwent treatment and were under outpatient monitoring in a hospital setting. The average age of the patients was 60.7±7.5 years. The expression of pan-B-cell antigens CD20, CD79A, PAX 5 (monomorphic intense nuclear expression), CD5, CD45, CD30, BCL-2, BCL-6, Ki-67, MUM1, GCET1, FOXP1 was examined in the patients. To exclude the polymorphic blastoid variant of lymphoma with CD5 expression in mantle cells, the study of cyclin D1 expression was conducted. Results: All patients began treatment with R-CHOP chemotherapy. In 37 cases, this regimen had to be replaced with DHAP in 23 (62.2%) patients due to the low effectiveness of the 1st-line chemotherapy, and in 14 (37.8%) after completing the full course (6 cycles) of treatment. Over the 6-year observation period, despite identical treatment, the 5-year survival rate was 60.5%. Among 32 (39.5%) patients, there was a fatal outcome due to the progression of the pathological process during treatment. Moderate expression was characteristic for the markers CD5, CD30, PAX-5, FOXP1, and GCET1, while high expression was observed for CD10, CD45, CD79A, Bcl-6, MUM1, and Ki-67. High expression of Bcl-2, Bcl-6, GCET1, and Ki-67 exceeding 60% is a prognostically unfavorable factor significantly impacting the survival of patients. The most unfavorable outcomes were observed with the combination of Bcl-2 and Ki-67 expression exceeding 60% along with CD-45. The combination of Ki-67 expression exceeding 60%, CD-79, and MUM1 also resulted in an unfavorable outcome in all cases. The prognostic scale, using Cox's proportional hazard, allows predicting the prognosis of diffuse large B-cell lymphoma with extranodal involvement with a probability of 87.2%. Conclusions: In our studies, it has been demonstrated that adverse immunohistochemical characteristics of diffuse large B-cell lymphoma with extranodal involvement include high expression of Bcl-2, Bcl-6, GCET1, and a Ki-67 proliferation index exceeding 60% (p<0.025).