Objectives: Prevention of sudden cardiac death is the number one clinical priority in sports cardiology. While the overall cardiovascular risk of long distance running is acknowledged as low, the frequency of cardiac arrests and sudden death has increased in middle-aged males during marathons since the year 2000. An evidence-based strategy for protecting susceptible runners from these acute cardiac events during races is considered based on identification of the underlying cause. Method: Review of articles in Pub Med on adverse cardiac events during marathons. Findings: Recent epidemiological studies have identified an increasing frequency of cardiac arrest in middle-aged males during marathons since the year 2000 with atherosclerotic heart disease as the main cause of sudden cardiac death. Same-aged asymptomatic middle-aged male physician-runners showed a post-race polymorphonuclear leukocytosis with sequential increases in interleukin-6 and C-reactive protein as a likely consequence of rhabdomyolysis after “hitting the wall”. Increased fibrinogen, von Willebrand factor and D-dimer with in vivo platelet activation indicated a concurrent hemostatic imbalance with pro-coagulant effects. Cardiac troponins I and T and NT-pro-B-type natriuretic peptide were elevated after races as additionally predictive of acute cardiac events in asymptomatic persons. Conclusions: High short-term risk for acute cardiac events in asymptomatic middle-aged male runners is shown by stratification of validated biomarkers, which may render non-obstructive coronary atherosclerotic plaques vulnerable to rupture during marathons. Pre-race aspirin usage is prudent to reduce these events mediated by atherothrombosis based on conclusive evidence for prevention of first acute myocardial infarctions in same-aged healthy male physicians. Prospective studies are needed to determine the efficacy of pre-race low-dose aspirin for curtailing the increasing frequency of race-related cardiac arrest and sudden death in susceptible runners.