Abstract: Background: HFpEF is a syndrome of chronic systemic inflammation that leads to endothelial dysfunction, myocardial stiffness and impaired functional capacity, all of which are driven by comorbidities. The connection between inflammatory biomarkers and peri-implantitis, a persistent biofilm-mediated inflammatory lesion around dental implants, is not known. Methods: This was an analytical cross-sectional study with 112 clinically stable HFpEF patients with at least one functional dental implant. Standardized protocols were used to evaluate peri-implant parameters, radiographic bone loss and systemic inflammatory markers. The patients were divided into two groups: Peri-implantitis (n = 44) and no peri-implantitis (n = 68). Results: Peri-implantitis was found in 39.3% of the participants. Compared with patients without peri-implantitis, affected patients had higher hsCRP (5.8 ± 2.7 vs. 3.2 ± 1.8 mg/L, p < 0.001), IL-6 (7.4 ± 3.1 vs. 4.6 ± 2.3 pg/mL, p < 0.001), TNF-alpha (14.2 ± 6.0 vs. 10.8 ± 4.7 pg/mL, p = 0.002), NLR (3.4 ± 1.2 vs. 2.6 ± 0.9, p < 0.001), fibrinogen (405 ± 85 vs. 351 ± 76 mg/dL, p = 0.001) and NT-proBNP (1078 ± 672 vs. 765 ± 510 pg/mL, p = 0.007). Multivariable adjustment did not alter the associations between peri-implantitis and hsCRP (β = 1.62 mg/L, p < 0.001), IL-6 (β = 1.84 pg/mL, p = 0.001) and high-inflammatory phenotype (adjusted odds ratio = 2.84, p = 0.017). Conclusion: Peri-implantitis was linked to greater systemic inflammatory burden in HFpEF patients, indicating that peri-implant inflammation could be a clinically relevant and modifiable comorbidity.