BACKGROUND: Levels of tumor necrosis factor-alpha (TNF-alpha) increase with acute ischemia. However, whether elevations of TNF-alpha in the stable phase after myocardial ischemia (MI) are associated with increased risk of recurrent coronary events is unknown. METHODS AND RESULTS: A nested case-control design was used to compare TNF-alpha levels obtained an average of 8.9 months after initial MI among 272 participants in the Cholesterol And Recurrent Events (CARE) trial who subsequently developed recurrent nonfatal MI or a fatal cardiovascular event (cases) and from an equal number of age- and sex-matched participants who remained free of these events during follow-up (controls). Overall, TNF-alpha levels were significantly higher among cases than controls (2.84 versus 2.57 pg/mL, P=0.02). The excess risk of recurrent coronary events after MI was predominantly seen among those with the highest levels of TNF-alpha, such that those with levels in excess of 4.17 pg/mL (the 95th percentile of the control distribution) had an approximately 3-fold increase in risk (RR=2.7, 95% CI 1.4 to 5.2, P=0.004). Risk estimates were independent of other risk factors and were similar in subgroup analyses limited to cardiovascular death (RR=2.1) or to recurrent nonfatal MI (RR=3.2). CONCLUSIONS: Plasma concentrations of TNF-alpha are persistently elevated among post-MI patients at increased risk for recurrent coronary events. These data support the hypothesis that a persistent inflammatory instability is present among stable patients at increased vascular risk. Novel therapies designed to attenuate inflammation may thus represent a new direction in the treatment of MI.