Surgical re-explorations represent 3–5% of all cardiac surgery. Concerns regarding mortality and major morbidity of re-explorations in the intensive care unit (ICU) setting exist. We sought to investigate whether they may have different outcomes compared with those performed in the operating room (OR). Single center retrospective review of patients who underwent mediastinal re-exploration in the ICU or in the OR after cardiac surgery. Mediastinal re-explorations were also classified as: “planned” and “unplanned”. Primary outcome was 30-day mortality, secondary outcomes include deep sternal wound infection (DSWI), sepsis, ICU and hospital length of stay, prolonged intubation (>72 h), tracheostomy, pneumonia, acute kidney injury requiring dialysis and stroke. Between 2010 and 2019, 195 of 7263 patients (2.7%) underwent mediastinal re-exploration after cardiac surgery. More patients in the ICU group experienced two or more re-explorations (30.3% vs. 2.3%, p < 0.001), a higher incidence of postoperative pneumonia (22% vs. 7%, p = 0.004), prolonged intubation (46.8% vs. 19.8%, p < 0.001) and longer hospital stay (30.3 ± 34.2 vs. 20.8 ± 18.3 days, p = 0.014). There were no differences in mortality between ICU and OR (16.5% vs. 13.9%, p = 0.24) nor in sepsis (14.7% vs. 7%, p = 0.91) and DSWI rates (1.8% vs. 1.2%, p = 0.14). Re-explorations in the ICU were not associated with increased mortality, sepsis and mediastinitis rate.