Background Despite significant advances in systemic therapy, the optimal surgical extent for locally advanced breast cancer (LABC) remains debated. While the Radical Mastectomy (RM) has largely been replaced by the Modified Radical Mastectomy (MRM), RM continues to be performed for select cases involving chest wall or pectoral muscle invasion. This multicenter prospective study compared the oncologic, functional, and quality-of-life outcomes of RM and MRM in patients with LABC treated in French tertiary centers. Methods A prospective comparative cohort study was conducted between January 2018 and December 2024 across three French surgical oncology centers. A total of 200 patients with stage IIIA–IIIC (T3–T4, N2–N3, M0) LABC were enrolled; 180 were analyzed after propensity matching (RM: n=90; MRM: n=90). All patients received neoadjuvant anthracycline–taxane chemotherapy, followed by either RM (Halsted–Meyer technique) or MRM (Patey/Auchincloss). Primary endpoints were Disease-Free Survival (DFS) and Overall Survival (OS); secondary endpoints included postoperative complications, functional recovery, and quality of life (QoL) assessed using the EORTC QLQ-C30/BR23 instruments. Statistical comparisons were made using the t-test, χ² test, Kaplan–Meier survival analysis, and Cox regression modeling (P < 0.05 significant). Results Baseline demographics were comparable between groups. RM was associated with longer operative time (132.6 ± 22.4 vs. 108.2 ± 18.5 min, P < 0.001) and higher morbidity (28.9% vs. 13.3%, P = 0.012). The 3-year DFS was 78.9% (RM) vs. 82.2% (MRM) (P = 0.47) and 3-year OS 86.7% vs. 89.4% (P = 0.52). Lymphedema (12.2% vs. 4.4%, P = 0.048) and shoulder stiffness (14.4% vs. 5.6%, P = 0.036) were significantly higher after RM. QoL scores favored MRM in physical, body image, and emotional domains (P < 0.001). Multivariate analysis identified tumor size ≥6 cm, lymphovascular invasion, and triple-negative subtype as independent predictors of recurrence, not surgical type. Conclusions In the era of neoadjuvant and adjuvant multimodal therapy, Modified Radical Mastectomy achieves equivalent oncologic outcomes to Radical Mastectomy while offering superior functional recovery and quality of life. RM should be reserved for patients with confirmed pectoral muscle or chest wall invasion. These findings support French and European surgical guidelines prioritizing muscle-preserving approaches as the standard of care for operable LABC.