Background: Neoadjuvant therapy (NAT) leads to a clinical complete response (cCR) in a significant proportion of patients with locally advanced rectal cancer (LARC) allowing for possible non-operative management. Along with physical exam and proctoscopy, magnetic resonance imaging (MRI) is used to evaluate for residual tumor following NAT. The presence of mucin on MRI leads to uncertainty about residual disease and appropriateness of watch-and-wait strategy (WW) in patients with no evidence of disease on proctoscopy (endoscopic cCR). We set out to determine the impact of radiographic mucin in patients with LARC after NAT. Methods: MRI reports between July 2016 to January 2020 at Memorial Sloan Kettering Cancer Center were queried for the presence of mucin in the tumor bed on post-treatment rectal MRI in patients with LARC following NAT. The clinicodemographic, pathologic, and outcomes data from these patients were compiled and analyzed. Results: Seventy-one patients were included in the final analysis who fit the pre-specified inclusion criteria (Table). Of the 71 patients with mucin present on post-treatment MRI, 19 patients (27%) entered a watch-and-wait (WW) strategy and 52 patients (73%) were planned for surgery (non-WW). Comparing the WW and non-WW cohorts, there was no difference in age, sex, clinical nodal status, or neoadjuvant regimen. Patients entering a WW protocol had a higher proportion of cT1-T2 tumors (32%) compared to non-WW (4%) (P < 0.01). All WW patients had endoscopic cCR, while only one non-WW patient achieved endoscopic cCR. Of 52 non-WW patients, 49 underwent resection and 3 did not have surgery due to disease progression. The pathologic complete response (pCR) rate in the non-WW patients who underwent surgery was 10%. Of 19 WW patients, 4 experienced regrowth (21%), while 15 (79%) have no local regrowth, with a median follow up of 4.2 years (range 2.4-6.3 yrs). Two patients (11%) experienced distant failure. Conclusions: The presence of mucin after NAT for LARC should not necessarily preclude a WW strategy in otherwise appropriate candidates who achieve an endoscopic cCR.