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Introduction: Patients with community-acquired pneumonia (CAP) are at increased risk of cardiovascular events; platelet activation has been suggested to play a role but the underlying mechanism is still unclear. Hypothesis: Our study hypothesis was that endotoxins (bacterial lipopolysaccharide, LPS) might play a role. Methods: Patients (n=100) with diagnosis of community-acquired pneumonia (CAP) through the emergency department (ED) and healty subjects (n=50) were consecutively recruited. Categorical variables were reported as counts (percentage) and continuous variables as means ± standard deviation (SD). The study was comprised 3 parts: 1) analysis of serum endotoxins in CAP patients versus controls; 2) ex vivo platelets aggregation in CAP patients and controls; 3) in vitro experiments to assess if LPS, in a range of concentrations detected in the blood of CAP patients, was capable of activating platelets. Results: CAP patients showed higher serum LPS and ex vivo platelet aggregation (PA) compared to controls. In in vitro study LPS, in a concentration (15-100 pg/ml) similar to that detected in human circulation of CAP patients, no changes of PA were detected. Conversely, LPS elicited PA if incubated with platelets stimulated with sub-threshold concentration of collagen or ADP; this effect was blunted in platelets pre-incubated with an inhibitor of toll-like receptor 4 (TLR4bp). LPS-mediated PA was associated with over-production of thromboxane (Tx) A2 and 8-iso-PGF2α-III, and was inhibited by aspirin or a TxA2 receptor antagonist. Platelet oxidative stress as assessed by measuring reactive oxygen species such as H 2 O 2 , and Nox2 activation was enhanced in LPS-treated platelets and reduced by the TLR4bp. Similarly, TLR4bp blunted the up-regulation of PLA2 phosphorylation, which was observed in LPS-treated platelets. Analysis of up-stream signaling potentially responsible for Nox2 and PLA2 activation demonstrated that LPS-mediated PA was associated with phosphorylation of AKT, p38 and p47 phox translocation. Conclusion: Together these data show that LPS amplifies the platelet response to common agonists via TLR4-mediated eicosanoid production and suggest endotoxemia as a potential trigger for PA in patients with pneumonia.