Duodenal adenocarcinoma (ADC) represents only 0.3% of gastrointestinal neoplasms. With the frequency being higher between the ages of 40 and 60, it is predominantly located in the second part of the duodenum and around the periampullary region. Symptoms are nonspecific, so the majority of patients present with advanced disease. Neoadjuvant chemotherapy is a therapeutic option that has not been well studied. The global literature includes only isolated reports on this subject. This is why we are presenting the following case: a 60-year-old female patient with a locally advanced, inoperable duodenal ADC received neoadjuvant chemotherapy. Having presented a favourable response as observed in the post-neoadjuvant extension studies, a pancreaticoduodenectomy was performed without any perioperative complications and with satisfactory progress. The final biopsy reported a complete pathological response. After being monitored for 34 months, the patient was free from locoregional and distant metastatic disease. During the last weeks of monitoring, she developed a second primary breast tumour, which has been corroborated by immunohistochemistry.