Abstract Background The association between mesotheliomas and ectopic ACTH secretion has been rarely reported; we present the first case of ectopic ACTH secretion (EAS) associated with a well-differentiated peritoneal mesothelioma in whom the high dose dexamethasone suppression test (HDDST) results and plasmatic ACTH levels were similar to those found in Cushing’s disease (CD). Case presentation A 43-year-old hispanic woman with a 20 year history of treatment resistant diabetes mellitus and arterial hypertension. She had a full moon face, a buffalo hump, increased volume in both supraclavicular regions, purple striae in her arms and abdomen, truncal obesity, polymenorrhea and umbilical hernia. A cortisol supression test with low dose dexamethasone (LDDST) with a result of 16.6 μg/dL and ACTH plasma levels were measured at 32.6 pg/mL. The high dose dexamethasone test suppression percentage was 84.8 % and magnetic resonance imaging (MRI) showed no evidence of pituitary alterations, computed tomography (CT) showed images suggestive of uterine fibroid and an intra-abdominal tumor that correlated with an umbilical hernia, which reinforcement after contrast. Surgery was performed, finding uterine fibroids and paracolic tumor implants as well as on the omentum, bladder, bowel, ovaries and appendix. Pathology reported a well-differentiated peritoneal mesothelioma with positive immunohistochemistry for ACTH. Conclusions Although most cases of ectopic secretion of ACTH derive from rapidly-developing lung tumors, with very high plasma ACTH levels and cortisol suppression percentages with high doses of dexamethasone under 60 %, there is a small percentage of slow-developing, chronic tumors that are biochemically undistinguishable from Cushing’s disease. Following the expert recommendations regarding imaging techniques it is possible to identify the associated tumor in most cases.