Preeclampsia (PE) is considered as one of the most severe pregnancy complications, an important role in pathogenesis of which is played by immunogenetic factors. The study aimed to assess the contribution of HLA-DR-dependent mechanisms to the immune response regulation in PE associated with the HLA-DRB1*01:01 allele carrier state in an in vitro experimental model. A comparative experimental in vitro study was conducted. Patients with PE (n = 7), who were HLA-DRB1*01:01 carriers, and women with the normal pregnancy course (NP; n = 10), who were not HLA-DRB1*01:01, -DRB1*04:01, -DRB1*10:01 carriers, were enrolled. The CD14+ and CD4+ cells, as well as placental tissue samples, from which the placental conditioned medium (PCM) was derived, were obtained from peripheral blood samples. The CD14+ and CD4+ cells were co-cultured in both groups. PCM was added to the culture to model the effects of placental factors. In the PE group, HLA-DR was blocked with the L243 monoclonal antibody; the IgG2a isotype antibody was used in the NP group. The share of Treg-cells in the cultures was determined by flow cytometry; the IL17, IFNγ, TNFα, IL10, and IL4 cocentrations were determined by ELISA. The direct CD14+ and CD4+ co-culture revealed no intergroup differences in the share of Treg and cytokine concentrations. The PCM supplementation in the PE group resulted in the decreased share of Treg and IL10 levels amid increasing IL17, TNFα, and IFN-γ. In the NP group, on the contrary, the increase in Treg counts, IL10 and IL4 levels, along with the decrease in IFN-γ levels was reported. The HLA-DR blockage in PE was associated with the decrease in IL17 and IFN-γ levels. The findings demonstrate the potential significance of placental factors and maternal immunogenetic features in the immune response regulation in PE.