Purpose <p>To identify computed tomography (CT) and clinical characteristics that may aid the radiologist and clinician in differentiating desmoid tumor from peritoneal metastasis in patients with a history of resected colon cancer.</p> Methods <p>This retrospective, single-center study included patients with resected colon cancer with one or more new peritoneal nodules on CT that then yielded pathology-proven desmoid tumor or peritoneal metastasis. Three radiologists, blinded to histopathology results, assessed peritoneal nodule characteristics on CT, including location, multiplicity, shape, contour, margin, density, homogeneity, presence of other metastatic disease, and size. Clinical characteristics assessed included age, biological sex, race, history of familial adenomatosis polyposis, carcinoembryonic antigen (CEA) level within 4 weeks of CT, time between colon cancer resection and diagnosis of either desmoid tumor or peritoneal metastasis, colon primary histology, and pathology TNM stage. Clinical characteristics as well as imaging characteristics (assessed by the most experienced radiologist) were tested for significance using Fisher’s exact test or Wilcoxon rank sum test.</p> Results <p>Of 30 patients (median age at colon cancer resection, 51 years [range, 20–79]; 18/30 (60%) male), 18/30 (60%) had desmoid tumor and 12/30 (40%) had peritoneal metastasis. On CT, location in the root of the mesentery and whorled margin were associated with desmoid tumor (<i>p</i> = 0.02 for both), and multiplicity and presence of other metastatic disease with peritoneal metastasis (<i>p</i> = 0.002 and 0.006). CEA &gt; 5 ng/mL was associated with peritoneal metastasis (<i>p</i> = 0.0005).</p> Conclusion <p>Some CT characteristics and elevated CEA may help differentiate desmoid tumor from peritoneal metastasis, guiding prognosis and disease management.</p>