Objective <p>Mediastinitis is a rare but highly morbid and mortal complication of cardiac surgery. This study aims to examine the potential perioperative risk factors associated with mortality among patients who developed mediastinitis following cardiac surgery with median sternotomy.</p> Methods <p>This retrospective study included 81 adult patients who developed mediastinitis following cardiac surgery with median sternotomy. Data on demographics, clinical/laboratory results, and mortality were extracted. Factors associated with mortality were examined. Comparative analyses were performed using appropriate parametric or non-parametric tests, depending on data distribution. Categorical variables were compared using the chi-square or Fisher’s exact test. Receiver operating characteristic analysis was used to assess predictive performance.</p> Results <p>Among the 81 mediastinitis patients included for analyses, 36 died and 45 survived. Based on multivariate analysis, use of blood or blood products (OR: 33.99; 95% CI: 1.84–626.78, <i>p</i> = 0.018) and increased serum procalcitonin levels reflecting disease severity during mediastinitis (OR: 1.62; 95% CI: 1.02–2.57, <i>p</i> = 0.039) were associated with higher mortality risk; on the other hand, higher serum albumin levels during the course of mediastinitis were associated with a lower risk of mortality (OR: 0.04; 95% CI: 0.00–0.28, <i>p</i> = 0.011). In further analysis, mortality was found to be higher in patients with serum albumin levels below 2.21&#xa0;g/dl, with a sensitivity of 86.1% and specificity of 86.7%.</p> Conclusions <p>Low serum albumin levels, blood and blood product use, and elevated procalcitonin levels were associated with increased mortality in poststernotomy mediastinitis, with serum albumin being the strongest prognostic marker.</p>