Aim: We aimed to compare the efficacy and the safety of cisplatin plus 5-FU plus trastuzumab and mFOLFOX-6 plus trastuzumab at first-line treatment in HER2-positive metastatic gastric cancer. Method: It was a retrospective observational monocentric study. Patients diagnosed with HER2-positive metastatic gastric adenocarcinoma between January 2013 and December 2020 in Dr AY Ankara Oncology TRH were screened. Patients treated at least one cycle of treatment with either CF-T or mFOLFOX-T were included. Survival outcomes and treatment compliance of patients were compared between groups. Results: Of 52 patients, 55.8% (n=29) of patients were treated with CF-T, and 44.2% (n=23) with mFOLFOX-T. The median age at diagnosis was 60 years (IQR: 52-70) in the CF-T and 64 years (IQR: 59-70) in the mFOLFOX-T groups. De novo metastatic disease comprised 96.6% (n=28) of patients in the CF-T and 69.6% (n=16) in the mFOLFOX-T groups (p=0.016). Both IHC3+ and ISH positivity were observed 82.8% (n=24) of patients in the CF-T and 56.5% (n=13) in mFOLFOX-T groups (p=0.038). The mPFS was 10.4 months (95% CI 8.7-12.2) in the CF-T and 6.5 months (95% CI 5.5-7.6) in the mFOLFOX-T groups (p=0.532). The mOS was 12.2 months (95% CI 11.3-13.2) in the CF-T and 12.5 months (95% CI 9.8-15.5) in the mFOLFOX-T groups (p=0.974). No statistically significant difference regarding at least one dose reduction (31.0% vs 21.7%, p=0.453) and at least one dose delay (24.1% vs 21.7%, p=0.838) was observed between groups. Conclusion: It was revealed that CF-T and mFOLFOX6-T had similar efficacy and tolerability in patients with HER2-positive metastatic gastric adenocarcinoma.