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Introduction and Importance: Situs inversus totalis (SIT) is a rare anatomical variation of the internal organs in which the thoracic and abdominal viscera organs are mirrored from their normal anatomical position. Surgical treatment of cancer in this anatomical variation represents a great challenge due to the altered surgical anatomic landmark. SIT has been related to a higher risk of cancer without evidences behind this hypothesis. Case Presentation: We report a 61-year-old male with SIT who presented with synchronous primitive pancreatic-head and lung cancers. After multidisciplinary discussion, it was decided to perform a pancreaticoduodenectomy for pancreatic cancer and radio-chemo-immunotherapy for lung cancer. Preoperative 3D reconstruction was performed to guide intraoperative navigation in mirrored anatomy, and as reported in previous studies preoperative 3D reconstruction may guide the evaluation of anatomic abnormalities. Clinical Discussion: In the literature, several studies discussed about the relationship between cancer and SIT concluding without a known link between these two conditions. The literature reported more than 200 cases of cancer in SIT, with only 21 cases of pancreatic cancer. Surgical treatment of cancer in SIT represents a challenge for surgeons. In this context, preoperative 3D reconstruction improves the early detection of anatomical variations and guide surgeons to a safer surgical approach. Conclusion: Although higher cancer risk has not clearly related to SIT, it should be assessed in these patients. The modified anatomy represents a challenge for surgeons, but technological tools like 3D reconstruction could improve the safety of surgery in mirrored anatomy.