Background: Periodontitis (PD) is classified by Grades A through C according to the risk of further progression, PD Grade C (PD-C) being the most severe progressing form. It is a matter of controversy, whether the disease activity observed in PD-C is due to impaired immune reactivity toward bacteria embedded in biofilms or a hyper-reactive immune response causing tissue damage as a bystander phenomenon. Little is known about the role of complement in this respect. Methods: Plasma and unstimulated saliva samples were collected from patients with PD-B (n = 34) or -C (n = 27) and healthy controls (HCs) (n = 28). Salivary and plasma levels of total C3, C3c, and C3dg were quantified using sandwich enzyme-linked immunosorbent assay (ELISA). Results: Salivary levels of total C3 and C3dg were elevated in PD-B and PD-C patients compared to HCs (both P < 0.05), while the levels of C3c were elevated in PD-C compared to HCs. Plasma levels of C3c were higher in PD-B patients than in HCs (P < 0.05). Conclusion: PD-B and PD-C patients show increased complement activation compared to HCs, but no difference was found between the two disease grades. PD-B, but not PD-C, is associated with increased systemic complement activation as assessed by C3c in plasma.