ABSTRACT Objective: Patients with locally advanced rectal cancer (LARC) need extensive surgical interference. Preoperative neoadjuvant chemoradiotherapy (CRT) shifts this extensive surgical procedure to another sphincter saving one as well as lowers patient’s morbidity and mortality. Till now, there is no definite method to predict patients’ response toneoadjuvant CRT Methods: REG IV and YKL-40 immunohistochemistry were evaluated in pre-treatment endoscopic biopsies from 42 LARC cases who received neoadjuvant CRT followed by surgical interference. The findings were correlated with the clinico-pathological features, tumor response, and tumor regression grade of the post-operative specimens. Results: REG IV high expression was associated with advanced post-treatment pathological tumor status, post-treatment pathological nodal status and presence of lympho vascular invasion with statistical significance. Furthermore, it was correlated witha lower extent of tumor regression after neoadjuvant CRT. All patients with pathological complete response exhibited negative/low REG IV expression and only 13.6% of theresponders showed high REG IV expression with statistical significance. YKL-40 immunohistochemicalexpression was highly associated with the tumor regression rate where of LARC patients with poor neoadjuvant CRT response highly expressed YKL-40 and66.6% of patients with complete regression showed negative/low expression of YKL-40. Conclusion: Our findings implicate REG IV and YKL-40 as important predictors of neoadjuvant CRT response in LARC.