BackgroundGrowing evidence suggests the type of periodontal treatment could differentially influence the reduction of key cardiovascular risk mediators in periodontitis patients. This randomized, controlled clinical trial compared the impact of minimally invasive non‐surgical therapy (MINST) with quadrant‐wise subgingival instrumentation (Q‐SI) on C‐reactive protein (CRP) together with lipoprotein‐associated phospholipase A2 (Lp‐PLA2) levels, and clinical periodontal outcomes in patients with periodontitis. Moreover, it was evaluated if baseline CRP levels impacted the efficacy of non‐surgical periodontal therapy protocols.MethodsForty‐two periodontitis patients were enrolled and randomly treated by means of MINST (n = 21) or Q‐SI (n = 21). The outcomes assessed were serum CRP and Lp‐PLA2, and periodontal parameters (probing depth [PD], clinical attachment level [CAL], full‐mouth bleeding score [FMBS]), at baseline and at follow‐ups at 1, 3, and 6 months and at 1 year after treatment.ResultsAt 1 year, MINST significantly reduced, among others, mean PD (p = 0.007), mean CAL (p = 0.007), the number of pockets >4 mm (p = 0.011) and ≥6 mm (p = 0.005), and FMBS (p = 0.048) compared to Q‐SI. Generalized multivariate analysis evidenced that high baseline CRP (p = 0.039) and FMBS (p = 0.046) levels, together with MINST treatment (p = 0.007) were significant predictors of PD reduction at 1‐year follow‐up. Moreover, the Jonckheere–Terpstra test showed that patients with high baseline CRP levels gained more benefits from MINST treatment at 1‐year follow‐up than they did from Q‐SI.ConclusionPatients receiving MINST showed a greater reduction in CRP levels than patients with Q‐SI after 1 year of follow‐up. Moreover, patients with high baseline levels of CRP and Lp‐PLA2 gained more benefits from the MINST approach at 1‐year follow‐up.