<p>The diagnosis of intra-abdominal infections (IAIs) is mainly clinical. Procalcitonin (PCT) is an acute phase protein widely used to assess bacterial infections, but no biomarker has proved to be a gold standard for sepsis. Thus, identifying a highly specific biomarker for early detection of abdominal infections would be valuable. Aim of the study was to provide a preliminary evaluation of the role of circulating calprotectin (C-CLP) in the diagnosis of IAIs by comparing it with PCT and assessing its correlation with disease severity. A series of adult patients admitted with a clinical (acute abdomen or SOFA ≥ 2) and a radiological (US or CT) evidence of IAI requiring surgery were enrolled. Based on the severity of the disease, patients were divided according to CPIRO score into group A (CPIRO ≤ 2) and group B (CPIRO ≥ 3). A control group (C) included patients undergoing elective abdominal wall surgery with no infection. A total of 151 patients were included: 78 in group A, 12 in group B, and 61 in group C. Baseline characteristics of groups were comparable with the exception of median age that was lower in group C (<i>p</i> = 0.006). Circulating calprotectin levels at the admission were significantly higher in groups A (2.8&#xa0;µg/mL) and B (4.6&#xa0;µg/mL) than in controls (0.6&#xa0;µg/mL, <i>p</i> &lt; 0.000001), as was PCT (<i>p</i> &lt; 0.000001). ROC analysis confirmed diagnostic accuracy for both biomarkers (C-CLP AUC = 0.899; PCT AUC = 0.936). An C-CLP cutoff &gt; 1.2&#xa0;µg/mL provided 82% specificity and 87% sensitivity. C-CLP correlated with CPIRO (<i>R</i> = 0.47), APACHE II (<i>R</i> = 0.46), and postoperative complications (<i>R</i> = 0.33). Circulating calprotectin demonstrated strong diagnostic accuracy for IAIs, comparable to PCT, and correlated with disease severity. Negative C-CLP values suggest infection is unlikely. These findings require confirmation in larger cohorts before clinical application.</p>