Background and Objective The complement system is engaged in inflammatory reactions both in the periodontal pockets and in the periodontium itself, where it can mediate tissue destruction. The aim of this study was, first, to compare salivary levels of the total complement system protein C3 and its split product, fluid-phase C3c in patients with periodontitis and periodontally healthy controls. Next, to determine if C3 and C3c levels had biomarker potential in diagnosing and monitoring periodontitis and its treatment. We hypothesized that salivary levels of total C3 and the split product C3c associated with the severity of periodontitis and reflected decreased inflammatory activity after periodontal treatment. Methods At baseline, stimulated saliva samples were collected from patients with periodontitis (n = 18) and periodontally healthy controls (n = 15). Subsequently, non-surgical periodontal treatment was performed in the patients, and saliva sampling from patients was repeated two-, six-, and twelve weeks post-treatment (NCT02913248 at clinicaltrials.gov). The patients were grouped as good and poor responders to treatment according to the achieved reduction in bleeding on probing (BOP). Salivary levels of C3 and C3c were quantified using sandwich ELISA. Results Patients with periodontitis had higher baseline levels of both total C3 and the split product C3c in saliva than did periodontally healthy controls (P <.0001). Receiver operating curve (ROC) analyses discriminated patients with periodontitis from controls based on both C3 (AUC (area under curve) = 0.91,P <.001) and C3c levels (AUC = 0.84,P <.001) in saliva. Periodontal treatment improved all clinical parameters (P <.01). Good responders (n = 10) had lower baseline levels of C3c than poor responders (n = 8), (P <.05), and baseline levels of C3c discriminated between good and poor responders (AUC = 0.80,P <.05). Conclusion In conclusion, patients with periodontitis had higher salivary levels of C3c, and the C3c levels were predictive of reductions in BOP, that is, the poor responders. This suggests that salivary C3c levels possess potential to serve as a biomarker predicting the clinical response to non-surgical periodontal treatment.