Background/Aim: This study evaluated clinicopathological and molecular features and their prognostic impact on patients with locally advanced rectal cancer (LARC) who received preoperative chemoradiotherapy (CRT). Patients and Methods: We retrospectively gathered data from 284 patients with LARC who underwent total mesorectal excision (TME) after CRT. Results: In the univariate analysis, lower yield pathologic T (ypT) category, yield pathologic N (ypN) category, yield pathologic TNM (ypTNM) stage, as well as the absence of lymphovascular invasion (LVI) and perineural invasion (PNI), were significantly associated with better disease-free survival (DFS) and overall survival (OS). Meanwhile, the expression of Ki-67, p53, and the mismatch repair (MMR) status showed no association with clinical outcomes. A multivariate survival analysis revealed that ypT category and LVI were independent prognostic factors of a worse DFS (HR=3.081, p-value=0.001; HR=2.818, p-value=0.030) and OS (HR=3.158, p-value=0.006; HR=3.837, p-value=0.014). Conclusion: The ypT category and the presence of LVI were found to be prognostic factors for patients with LARC after CRT followed by TME. Locally advanced rectal cancer (LARC), characterized by invasion of tumors beyond muscle layers or metastasis of regional lymph nodes at diagnosis, shows poor prognosis, and approximately one third of patients eventually experience distant metastases (1). Neoadjuvant chemoradiotherapy (CRT) in LARC is known to have advantages for anal sphincter preservation, preoperative downstaging of the tumor, lower local recurrence rate, and fewer toxicities related to treatment compared with adjuvant CRT (1, 2). Therefore, neoadjuvant CRT followed by surgical excision is recommended as standard treatment for patients with LARC. Despite the adoption of neoadjuvant CRT in LARC management, the treatment response has remained varied. Around 15% of patients treated with neoadjuvant CRT achieve pathologic complete response (pCR), with the remaining of them exhibiting various pathologic responses from tumor downstaging to distant metastatic disease. The varied treatment responses imply that rectal cancer is a heterogeneous disease, and its unidentified clinicopathological features may be responsible for the different clinical outcomes such as recurrence, metastasis, or survival. Pathological stages after surgical resection and following neoadjuvant CRT are universally classified by ypStage, which has been considered a robust prognostic indicator of LARC (3, 4). In addition, pathological residual lymph node metastasis and invasion depth of the tumor after neoadjuvant CRT have been confirmed to be major prognostic factors of rectal cancer and are strongly correlated with metastasis and disease-free survival (DFS) (3-6). Previous studies have demonstrated that the presence of lymphovascular invasion (LVI), or perineural invasion (PNI), has a negative impact on clinical long-term outcomes (7). Recently, molecular markers were studied as prognostic factors to predict CRT response ...