Background <p>The study aimed to identify the prognostic factors affecting survival among patients with duodenal adenocarcinoma (DAC) and isolated hepatic metastases (HM).</p> Methods <p>We conducted a retrospective analysis of clinical data from 51 patients treated for DAC and HM from January 2012 to January 2018. The Kaplan–Meier method and log-rank test were used for survival analysis. The Cox proportional hazards regression model was utilized for multivariate analysis.</p> Results <p>Thirty-nine patients had synchronous HM, and 12 patients exhibited metachronous HM. Median overall survival (mOS) for patients with synchronous HM was 6.8 months, versus 45.9 months for those with metachronous HM (<i>P</i> &lt; 0.001). mOS for the patients who received first-line chemotherapy was 18.9 months, compared with 4.4 months for the patients who did not undergo first-line chemotherapy (<i>P</i> &lt; 0.001). Multivariate analysis identified the timing of HM detection and the receipt of first-line chemotherapy as independent prognostic factors. Subgroup analysis revealed that among patients with synchronous HM, mOS for patients who underwent primary tumor resection was 16.9 months, compared with 3.5 months for those who did not undergo resection (<i>P</i> &lt; 0.001).</p> Conclusion <p>The timing of detection of HM and the receipt of first-line chemotherapy are independent prognostic factors for patients with DAC and isolated HM.</p>