Many inflammatory and infectious entities may acutely affect the peritoneum causing a thickening of its layers. Unfortunately, several acute peritoneal diseases can have overlapping features, both clinically and at imaging. Therefore, the awareness of the clinical context, although useful, may be sometimes insufficient to identify the underlying cause. This article provides a specific computed tomography-based approach including morphologic characteristics of peritoneal thickening (e.g., smooth, irregular, or nodular) and ancillary findings to narrow the differential diagnosis of acute peritonitis.