<p>Periodontitis is a highly prevalent chronic inflammatory disease that causes progressive destruction of the tooth-supporting apparatus and is linked to multiple systemic disorders. Despite its high prevalence, early biomarkers capable of predicting individual susceptibility remain elusive. The multifactorial nature of the disease and the lack of a validated, specific indicators hinder reliable early diagnosis before irreversible tissue damage occurs. CD5⁺ B cells, known for their autoreactive potential and role in bone resorption, have been previously found elevated in advanced periodontitis. Due to their association with tissue destruction, these cells may hold predictive value even at earlier stages. However, their systemic relevance in early periodontal inflammation is scarcely explored. This cross-sectional study examined differential subsets of circulating CD5⁺ B cells as potential systemic biomarkers of early periodontal disease. Sixty patients were grouped as healthy, gingivitis and moderate chronic periodontitis. Multiple regression analysis revealed that besides age (<i>p</i> = 0.009), the double negative (CD27⁻IgD⁻) subset of CD5⁺ memory B cells was related to periodontitis, while total CD5⁺ B cell levels remained unchanged. To characterize the oral inflammatory milieu, salivary cytokines and the composition of the subgingival microbiome were analyzed. Salivary IL-8 levels and IL-17A detection rates were significantly elevated in periodontitis. Microbiome profiling further identified an exploratory correlation between <i>Megasphaera</i> and salivary IL-8 in gingivitis, which may represent an early-stage signal but requires validation in larger follow-up cohorts.</p>