Background: This study was designed to assess the capability of perioperative ctDNA analysis to predict surgical outcome and recurrence following neoadjuvant CRT for LARC. Methods: Thirty-one patients (pts) with newly diagnosed LARC (n = 29) or locally recurrent (non-metastatic) rectal cancer (n= 3) were treated between 7/2013 - 7/2017. Pts received long-course neoadjuvant CRT prior to surgical resection: 50.4 Gy/28 fractions. Serum ctDNA was typically measured at baseline, weekly during CRT, pre-operatively, and post-operatively. Next-generation sequencing was used to identify mutations in the primary tumor, and mutation-specific droplet digital PCR was used to detect mutation fraction in ctDNA. Results: The median age of the cohort was 53 years (IQR 46.5-65.3 y). The overall R0-node negative (R0-NN) resection rate was 66.7%. The rate of R0-NN resection was significantly higher among pts with undetectable preoperative ctDNA (n = 17, 88%) compared to pts with a detectable preoperative ctDNA (n = 10, 30%, Fisher’s exact p = 0.036). The overall pathologic complete response (pCR) rate was 18.5%. The pCR rate among pts with undetectable preoperative ctDNA was 23.5% vs 10% among pts with detectable preoperative ctDNA (ns). For patients with a positive assay at baseline and weekly draws available, those who went on to have an R0NN resection were observed to exhibit ctDNA clearance by the second week of chemoradiation. Recurrence free survival (RFS) was calculated for the subset (n= 22) who were able to undergo surgery and had post-operative ctDNA available. Pts with detectable postoperative ctDNA experienced poorer RFS than those with undetectable ctDNA, HR 8.0, p< 0.001. Conclusions: Undetectable preoperative ctDNA is associated with R0-NN surgical outcome, and detectable postoperative ctDNA is associated with worse RFS in a cohort of pts treated with neoadjuvant CRT for LARC. Validation is ongoing in a larger cohort of 39 pts.