<p><b>Objective.</b> To evaluate the effectiveness of comprehensive rehabilitation measures using the peptidergic drug Cortexin in children with perinatal CNS injury (PCNSI) based on assessment of serum levels of proinflammatory cytokines. <b>Materials and methods.</b> A total of 146 children (86 boys and 60 girls) aged 20 days to 6 months (mean age in boys 2.7 ± 1.2 months, mean age in girls 2.9 ± 1.1 months) with PCNSI were examined. Depending on the severity of PCNSI, patients were divided into three groups: Group 1 (<i>n</i> = 50) included patients with severe PCNSI, Group 2 (<i>n</i> = 58) included patients with moderately severe PCNIS, and Group 3 (<i>n</i> = 38) included patients with mild PCNSI. Each group was randomly divided into two subgroups. Patients in subgroups 1A, 2A, and 3A were prescribed Cortexin in addition to standard therapy administered in accordance with current clinical guidelines. Patients in subgroups 1B, 2B, and 3B received standard therapy alone. Serum TNF-α and IL-Iβ concentrations were measured during treatment. <b>Results.</b> In subgroup 1A, IL-Iβ concentrations decreased by a factor of 1.5 (<i>p</i> = 0.022) and TNF-α by a factor of 1.4 (<i>p</i> = 0.033) after treatment; these changes were statistically significantly greater than those in subgroup 1B. In subgroup 2A, IL-Iβ concentrations decreased by a factor of 1.4 and TNF-α by a factor of 1.2 (<i>p</i> = 0.038) compared to baseline values by month 3 (<i>p</i> = 0.037), whereas no correction in the cytokine level was observed in patients in subgroup 2B. In subgroup 3A, changes in IL-Iβ and TNF-α concentrations were more marked than those in subgroup 3B. <b>Conclusions.</b> Inclusion of Cortexin in treatment of patients with PCNSI of different severities led to significant shifts in IL-Iβ and TNF-α levels three months after treatment initiation, which was significantly greater than obtained with standard treatment.</p>