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 morbid¬ity and mortality. Till now, there is no definite method to predict patients’ response to neoadjuvant 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 sur¬gical 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 patho-logical tumor status, post-treatment pathological nodal status and presence of lym¬pho-vascular invasion with statistical significance. Furthermore, it was correlated with a lower extent of tumor regression after neoadjuvant CRT. All patients with pathologi¬cal complete response exhibited negative/low REG IV expression and only 13.6% of the responders showed high REG IV expression with statistical significance. YKL-40 immuno¬histochemical expression was highly associated with the tumor regression rate where 85% of LARC patients with poor neoadjuvant CRT response highly expressed YKL-40 and 66.6% 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 neoad¬juvant CRT response in LARC.