An imbalance of different parts of the antiviral immune response system associated with deficits of type I and type II interferons (IFN) is commonly observed in atypical chronic active herpesvirus infections (ACA-HVI). Objective. To develop a clinical and immunological diagnostic algorithm for detecting the pathological immunophenotypes of ACA-HVI. Patients and methods. A total of 263 male and female patients aged 23–70 years with ACA-HVI were examined. The study included the following methods for herpesvirus detection: serodiagnostics and a real-time polymerase chain reaction (RT-PCR). The cytokine profile (interleukins IL-1β, IL1Ra, IL-6, IL-17, TNFα) and the IFN system were analyzed by an enzyme-linked immunosorbent assay (ELISA). The study was approved by the Ethics Committee, and an informed consent was obtained from all patients. Results. To assess the clinical signs of immunosuppression in patients with ACA-HVI, we formulated de novo clinical criteria of class I and class II and used them in the study. Based on the three main pathological immunophenotypes identified, we created an algorithm for the clinical and laboratory diagnosis of ACA-HVI. It was shown that determining the serum levels of cytokines IL-1β, IL-6, IL1Ra and tumor necrosis factor-α is the most optimal option to assess the level of systemic inflammation and neuroimmune inflammation. Conclusion. The findings of the immunological study allowed us to identify variants of pathological immunophenotypes, which are characterized by the variability of the detected disorders. The revealed disorders in the immune system and IFN system in each pathological immunophenotype are associated with certain ACA-HVI manifestations, typical of study groups 1, 2, 3. © 2023, Dynasty Publishing House. All rights reserved.