Background: Mucinous adenocarcinoma and signet-ring cell carcinoma were uncommon in locally advanced rectal cancer. And it has been reported that both mucinous adenocarcinoma and signet-ring cell carcinoma showed poor response to standard neoadjuvant chemoradiotherapy. Here, we tried to compare the efficacy of different neoadjuvant treatment regimen on locally advanced rectal mucinous adenocarcinoma or signet-ring cell carcinoma (M/S). Methods: We enrolled patients with locally advanced rectal cancer from 3 prospective clinical trials (NCT01211210, NCT02217020 and NCT02887313), including FOWARC study (N = 309), mFOLFOXIRI neoadjuvant chemotherapy trial (N = 103) and the total neoadjuvant treatment with FOLFOX and radiotherapy (N = 129). Among the 541 patients, 41 (7.6%) patients were M/S and 500 were non-M/S. Totally, 7 M/S patients and 84 non-M/S patients received 5FU concurrent with radiotherapy (Group A), 20 M/S patients and 208 non-M/S underwent FOLFOX concurrent with radiation or total neoadjuvant treatment (Group B), 11 M/S patients and 92 non-M/S patients underwent mFOLFOXIRI neoadjuvant chemotherapy alone (Group C). Other 3 M/S patients and 116 non-M/S patients received FOLFOX neoadjuvant chemotherapy alone (Group D). Results: Among M/S patients, only 4 (9.7%) achieved pathologic complete response (pCR), and 6 (14.6%) patients had tumor downstaging to ypstage 0-I. In group A, the pCR rate was 14.3% and 11.9% (p = 0.85), and the tumor downstaging rate was 14.3% and 36.9% (p = 0.22) in M/S and non-M/S patients, respectively. In group B, the pCR rate was 15.0% and 34.6% (p = 0.07), and the tumor downstaging rate was 25.0% and 60.1% (p = 0.002) in M/S and non-M/S patients, respectively. However, in group C and group D with chemotherapy alone as neoadjuvant treatment, no M/S patients showed pCR or tumor downstaging; while in non-M/S patients higher tumor downstaging rate was observed. Conclusions: M/S showed resistance to neoadjuvant chemotherapy along regimens. Even with chemoradiotherapy, M/S patients showed poorer response than that of non/M/S patients. Further study was warranted to explore the new regimen for M/S patients.