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BACKGROUND The predictive value of sarcopenia for tumor response to neoadjuvant chemoradiotherapy is unclear. OBJECTIVE This study investigates the association between sarcopenia and pathological tumor regression grade after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. DESIGN Retrospective cohort study from a prospectively collected database. Univariate logistic regression was performed to assess the association between sarcopenia and tumor response. SETTINGS This study was conducted at two tertiary care centers. PATIENTS Patients undergoing neoadjuvant chemoradiotherapy for locally advanced rectal cancer (T3/4, N0/+) between 2007-2018. INTERVENTION Sarcopenia was diagnosed using gender-specific cut-offs of lean muscle mass. Using the initial staging computed tomography, lean muscle mass was estimated using the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra, normalized for patient height. MAIN OUTCOME MEASURES The primary endpoint was pathological tumor regression grade, defined as good (Tumor regression grade 0/1) vs poor (Tumor regression grade 2/3). RESULTS The study included 167 locally advanced rectal cancer patients with a median age of 60 years (20-91), 132 in the non-sarcopenia group, and 35 in the sarcopenia group. Eighty-nine percent were stage III. Six patients (5.4%) had a sustained complete clinical response, one patient did not respond to treatment and opted for nonoperative management, the remaining 157 (94.0%) proceeded to surgery. Pathological data revealed no significant difference between good tumor regression grade patients in the sarcopenia group compared with the non-sarcopenia group. Univariate analysis revealed BMI≥ 25 kg/m2 to be risk factors for good tumor regression grade (p = 0.002). LIMITATIONS This study was limited by its retrospective design and small sample size. CONCLUSION Sarcopenia is not a predictor of poor neoadjuvant chemoradiotherapy response in locally advanced rectal cancer patients. Increasing BMI was associated with good tumor regression grade. Future multicentered studies are warranted to validate this finding. See Video Abstract at http://links.lww.com/DCR/C78.