Background <p>Less than 10% of breast cancer patients have distant metastatic lesions (DnMBC) at the time of diagnosis. The overall survival (OS) of this group has been prolonged by advances in systemic therapies (ST) in recent decades. This study aimed to evaluate the role of locoregional treatment (LRT) in de novo metastatic breast cancer (DnMBC), which is non-progressive under ST.</p> Methods <p>The DnMBC patients who did not progress under ST were randomized to LRT and ST groups. The LRT group underwent a free-margin lumpectomy or mastectomy and axillary surgery with or without adjuvant radiotherapy. All the patients received maintenance ST thereafter and were visited every 3 months. The primary endpoint was OS.</p> Results <p>Between 2018 and 2023, 250 patients were randomly assigned between the LRT (<i>n</i> = 158) and ST (<i>n</i> = 92) groups. The two groups were similar in terms of age and subtype. A 2-year OS of 81% and a 5-year OS of 43% were observed in the entire cohort. The estimated median time to death was 53 months (95% confidence interval [CI], 45–61 months) in the LRT group and 55 months (95% CI, 44–66 months) in the ST group. The log-rank test (<i>p</i> = 0.6) and adjusted Cox regression (hazard ratio [HR], 0.08; 95% CI, 0.9–1.3; <i>p</i> = 0.35) showed no OS differences between the LRT and ST groups. Patients with human epidermal growth factor receptor 2 (HER2+) (HR, 1.86; 95% CI, 1.21–2.87; <i>p</i> = 0.005) and lung metastasis (HR, 1.5, 95% CI, 1.04–2.26, <i>p</i> = 0.03) had an increased risk of death.</p> Conclusion <p>In DnMBC, LRT is not associated with improved&#xa0;OS. Those with lung metastasis and HER2+ disease had a higher risk of death.</p>