Objective: This study aimed to investigate the clinical outcomes of site-specific therapy (SST) in patients with metastatic adenocarcinoma of unknown primary (MACUP). Material and Methods: A retrospective observational study was conducted, including patients diagnosed with MACUP. Clinicopathological features and clinical outcomes of SST were evaluated. Results: Sixty patients were included in the study. The median age was 61.5 (minimum-maximum: 31.1-76.1) years, and 40.0% of the patients (n=24) were 65 years or older. The progression- free survival (mPFS) was 4.7 months [95% confidence interval (CI): 3.7-5.7] with the first-line treatment in the whole group. The mPFS was 4.1 months (95% CI: 2.9-5.2), 4.7 months (95% CI: 3.0-6.3), and 9.3 months (95% CI: 6.1-12.6) in the gemcitabine plus cisplatin, carboplatin plus paclitaxel, and mFOLFOX-6 groups, respectively. The overall survival (mOS) was 14.1 months (95% CI: 9.2-18.8) in the whole group. The mOS was 9.2 months (95% CI: 3.3-14.3), 8.5 months (95% CI: 3.8-13.2), and 15.5 months (95% CI: 9.3-18.8) in the gemcitabine plus cisplatin, carboplatin plus paclitaxel, and mFOLFOX-6 groups, respectively. Conclusion: Patients with colorectal-derived cancers of our cohort, considered as a “more sensitive” type, seemed to benefit more from immunohistochemistry-based (IHC-based) SST. However, SST determination using genomic profiling is a gold standard, and IHC also offered valuable information.