Background <p>Although current guidelines recommend total neoadjuvant therapy as the initial treatment for patients with high-risk locally advanced rectal cancer, its adoption remains controversial in certain populations due to the various adverse effects associated with radiotherapy.Currently, there is a paucity of studies directly comparing total neoadjuvant therapy(TNT)with neoadjuvant chemotherapy alone(NACT) for the management of high-risk mid/upper locally advanced rectal cancerLARC.</p> Methods <p>Between January 2017 and December 2022, eligible patients admitted to our institution were included in the study. We retrospectively compared the two groups regarding postoperative pathological response, surgical outcomes, prophylactic enterostomy, postoperative complications, and survival outcomes.</p> Results <p>A total of 391 patients were included in the propensity score matched (PSM) analysis. After PSM, 294 patients (147 pairs) remained, the TNT group demonstrated a higher pathological complete response (pCR) rate compared to the NACT group (23.81% vs. 8.84%, <i>p</i>=0.007), as well as a more favorable tumor regression grade (TRG) (<i>p</i>&lt;0.001). However, the TNT group also had a higher rate of prophylactic enterostomy (<i>p</i>&lt;0.001). While there was no significant difference in overall postoperative complications between the groups (<i>p</i>=0.138), the incidence of anastomotic fistula was significantly higher in the TNT group (p=0.008). Regarding survival outcomes, no significant differences were observed between the TNT and NACT groups in terms of disease-free survival (DFS, <i>p</i>=0.285) or overall survival (OS, <i>p</i>=0.906).</p> Conclusions <p>For patients with high-risk mid/upper LARC, NACT may serve as a potential therapeutic alternative.</p>