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BACKGROUND A penetrating injury to the “cardiac box” is thought to be predictive of an injury to the heart; however, there is very little evidence available to support this association. This study aims to evaluate the relationship between penetrating trauma to the cardiac box and a clinically significant injury. METHODS All patients presenting to a Level I trauma center from January 2009 to June 2015 who sustained a penetrating injury isolated to the thorax were retrospectively identified. Patients were categorized according to the location of injury: within or outside the historical cardiac box. Patients with concurrent injuries both inside and outside the cardiac box were excluded. Clinical demographics, injuries, procedures, and outcomes were compared. RESULTS During this 7-year period, 330 patients (92% male; median age, 28 years) sustained penetrating injuries isolated to the thorax: 138 (42%) within the cardiac box and 192 (58%) outside the cardiac box. By mechanism, 105 (76%) were stab wounds (SW) and 33 (24%) were gunshot wounds (GSW) inside the cardiac box, and 125 (65%) SW and 67 (35%) GSW outside the cardiac box. The overall rate of thoracotomy or sternotomy (35/138 [25.4%] vs. 15/192 [7.8%], p < 0.001) and the incidence of cardiac injury (18/138 [13%] vs. 5/192 [2.6%], p < 0.001) were significantly higher in patients with penetrating trauma within the cardiac box. This was, however, dependent on mechanism with SW demonstrating a higher incidence of cardiac injury (15/105 [14.3%] vs. 3/125 [2.4%], p = 0.001) and GSW showing no significant difference (3/33 [9.1%] vs. 2/67 [3%], p = 0.328]. There was no difference in overall mortality (9/138 [6.5%] vs. 6/192 [3.1%], p = 0.144). CONCLUSION The role of the cardiac box in the clinical evaluation of a patient with a penetrating injury to the thorax has remained unclear. In this analysis, mechanism is important. Stab wounds to the cardiac box were associated with a higher risk of cardiac injury. However, for GSW, injury to the cardiac box was not associated with a higher incidence of injury. The diagnostic interaction between clinical examination and ultrasound, for the diagnosis of clinically significant cardiac injuries, warrants further investigation. LEVEL OF EVIDENCE Prognostic study, Level IV, Therapeutic V.