Background: Immune-related adverse events (irAEs) occur in up to 50% of patients treated with immune checkpoint inhibitors (ICI). Severe forms of toxicity are observed in 3% of patients and require systemic steroid therapy and constant monitoring. One of the considered predictor biomarkers of irAEs development is HLA-genotypes. This research aims to evaluate the diagnostic significance of HLA-DRB1 genotypes and other clinical, laboratory parameters to predict the development of irAEs. Methods: The study involved 28 patients (pts) with metastatic melanoma taking ICI (nivo 53.6%, ipi+nivo 32.1%, other 14.3%). The PD-L1 expression, HLA-DRB1 genotype were evaluated. After 2-3 months the development of irAES was assessed. The complications of 3-4 grade or multi-organ damage were termed as a severe irAEs. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using Fisher, Mann-Whitney, ROC statistical analysis. The project is supported by a grant (14. W03.31.0009). Results: Different IrAEs developed in 57.1% (16/28) of patients, while severe irAEs in 35.7% (10/28). Among all patients HLA-DRB1 genotypes associated with the risk of autoimmune diseases were found in 78.5% (22/28). The PD-L1 expression was detected in 60.7% (17/28) of individuals.Combination treatment increases the risk of toxicity, p = 0.003, with a diagnostic sensitivity (S) of 56% and a diagnostic specificity (Sp) of 100% (RR = 2.71, OR = 31.67). The analysis of specific complications revealed associations between HLA-DRB1*04 with diabetes mellitus, p = 0.026 (OR = 33.57, S = 100%, Sp = 88.5%), HLA-DRB1*04/15 with autoimmune hepatitis or increased transaminases, p = 0.037 (OR = 17.27, S = 100%, Sp = 72%). An index based on the parameters studied (HLA-DRB1, the absence of PD-L1 expression, type of treatment) was created. With index value ≥2 a sensitivity for predicting severe toxicity is 40.00% and a specificity is 83.33%, p = 0.0126. Conclusions: According to the results obtained it can be assumed that the development of severe forms of irAES has a multifactorial origin, in particular, combination therapy, the absence of PD-L1 expression, which can lead to the loss of ICI drug specificity, and the presence of HLA-DRB1 genotypes associated with the risk of developing autoimmune diseases. The new diagnostic index to predict severe complications based on these parameters was created and showed a sensitivity of 40.00% and a specificity of 83.33%. The authors consider the limitations of the study, such as the small sample, the short observational period.