This study tested the hypothesis that activated toll-like receptor-4 (TLR-4) is closely related to combined major adverse clinical outcomes (MACO) [defined as advanced Killip score (≥ 3), overt congestive heart failure (CHF) (New York Heart Association functional class ≥ 2) or 30-day death] in patients with ST-segment elevation (ST-se) acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI). We conducted a prospective cohort study in 43 consecutive patients with ST-se AMI of onset < 12 hours who were undergoing primary PCI. Blood samples for TLR-4 and serum level of tumor necrosis factor-α (TNF-α) were collected from 43 patients at 24 hours after AMI and from 20 normal outpatients. The experimental results revealed significantly higher baseline levels of TLR-4, TNF-α and white blood cell (WBC) count in the study patients than in normal control subjects (all P < 0.0001). Additionally, baseline levels of TLR-4, TNF-α , creatinine, peak level of CK-MB, and multiple vessel disease were significantly higher, whereas left ventricular performance was notably lower in patients (n = 18) with occurrence of MACO than in patients (n = 25) without occurrence of MACO (all P < 0.05). Furthermore, the level of lipopolysaccharide (LPS)-stimulated LTR-4 was significantly increased in MACO patients than in those without MACO (P < 0.0001). Moreover, LPS-stimulated TLR-4 was the most independent predictor of 30-day MACO (P < 0.01). In patients with ST-se AMI, activated TLR-4 is independently predictive of 30-day MACO.