Background: The necessity for changing the postoperative therapy regimen for locally advanced gastric cancer after ineffective neoadjuvant chemotherapy and surgery is unclear because there are no criteria to determine which patients can benefit from this treatment. We assessed whether graded histologic regression of <50% could be the criterion for regimen modification. Methods: The study was designed as a matched-pair case-control investigation to minimize intergroup heterogeneity. Patients were stratified into two groups in which they either continued in the same course of treatment or changed the regimen to neoadjuvant chemotherapy. Results: Thirty-six patients were stratified into two groups. The adjuvant chemotherapy regimen of 12 patients was changed, while 24 patients continued on the same regimen. During an average follow-up period of 36 months, there was no difference observed in overall survival in the two groups (median, 24.0 vs. 31.0 months, P=0.863). In a subgroup analysis, however, patients in the changed regimen group with ypTNM stage III disease tended to have superior overall survival, though this effect was not significant (median, 23.0 vs. 14.0 months, P=0.123). Post-therapy nodal status was associated with overall survival in the multivariate analysis (P=0.014, HR 12.503, 95% CI: 1.664-93.919). Most adverse events were categorized as grade 1 or 2, and all treatments were well tolerated. Conclusions: Changing treatment based on a graded histologic regression of <50% after neoadjuvant chemotherapy did not prolong overall survival in patients with gastric cancer. However, changing the adjuvant regimen did reveal a trend towards improved overall survival in the ypTNM stage III subgroup, which merits further investigation using a larger sample size.