Platelet factor 4 (PF4) and heparin (H) form PF4/H complexes, the target of the immune reaction in heparin-induced thrombocytopenia (HIT). HIT seems to be a secondary immune response as anti-PF4/H-IgG antibodies occur as early as day 4 of heparin treatment. This study investigated whether prevalent infections such as periodontitis may induce the PF4/H immune response as: (1) natural anti-PF4/H Abs are present in the normal population; (2) PF4 bound to bacteria exposes the same antigen(s) as PF4/H complexes; and (3) sepsis induces PF4/H Abs in mice. We found PF4 bound to periodontal pathogens (Aggregatibacter actinomycetemcomitans; Porphyromonas gingivalis) enabling subsequent binding of human anti-PF4/H Abs. The association of natural PF4/H Abs and periodontitis was assessed in a case-control study, enrolling individuals with natural anti-PF4/H Abs (n = 40 matched pairs), and in the cross-sectional population-based Study of Health in Pomerania (SHIP; n = 3500). Both studies showed a robust association between periodontitis and presence of anti-PF4/H Abs independent of inflammation markers (case-control study: lowest vs highest tertile, odds ratio, 7.12 [95% confidence interval, 1.73-46.13; P = .005]; SHIP study, p(trend) ≤ 0.001). Thus, preimmunization to PF4/bacteria complexes by prevalent infections, for example, periodontitis, likely explains the presence of natural anti-PF4/heparin Abs and the early occurrence of anti-PF4/H-IgG in HIT.