Evidence suggests that individuals with Down syndrome (DS) have a high prevalence of periodontal disease (PD). Factors such as muscular hypotonia, macroglossia, intellectual deficits, and reduced motor coordination, often combined with inadequate dietary habits, contribute to the development of PD. Additionally, a compromised immune response may explain the altered inflammatory profile that affects the systemic and oral health of this population. This study aimed to analyze the relationship between serum levels of inflammatory cytokines (IFN-γ, IL-10, IL-17, IL-1β, IL-4, and TNF-α) and the severity of periodontitis in individuals with DS. We conducted a case-control study involving individuals with DS (n = 43) and non-syndromic individuals (n = 20). All participants underwent a clinical periodontal examination that included measurements of probing pocket depth (PPD), clinical attachment level (CAL), gingival bleeding index (GBI), and visible plaque index (VPI). Participants were classified into stages of periodontitis: stage 1 and stages 2-4, forming two subgroups within both the case and control groups. Serum levels of IFN-γ, IL-10, IL-17, IL-1β, IL-4, and TNF-α were compared between subgroups and analyzed as continuous variables for independent samples. We compared the four subgroups while considering the stage of periodontitis and the presence of DS. The relationship between DS and the stages 2-4 periodontitis with inflammatory marker levels was analyzed using linear regression models, adjusted for age and sex. The results showed no association between periodontitis severity and serum cytokine levels in any of the subgroups (P >
0.05). However, DS was associated with reduced serum levels of IFN-γ and increased serum levels of IL-10, IL-1β, IL-4, and TNF-α (P <
0.05). These findings suggest that individuals with DS have increased serum levels of inflammatory cytokines compared to non-syndromic individuals, regardless of the severity of periodontitis.