Background: Preoperative induction chemotherapy followed by chemoradiation yields better R0 resection rates, pathologic complete response (pCR) rates and improved survival for localized GAC.Previous studies with two-drug induction chemotherapy showed 70-80% R0 resection rates and 20-30% pCR rates. We report the effect of three-drug induction chemotherapy on a large cohort of localized GAC patients. Methods: We identified 97 patients with localized GAC who received three-drug induction chemotherapy followed by preoperative chemoradiation therapy. We assessed various endpoints (overall survival [OS], recurrence-free survival [RFS], R0 resection and pCR rate). Results: The median follow-up time was 3.5 years (range; 0.4-16.7). Most of the patients were men (60.8%) and the median age was 60 years (range; 21-89). The induction chemotherapy regimen was a fluoropyrimidine and a platinum compound (cisplatin or oxaliplatin) with a taxane (docetaxel or paclitaxel) for 95% of patients. Seventy-three (75%) out of 97 patients underwent planned surgery. R0 resection and pCR rate were 93% and 21%, respectively. Pathologic partial response (< 50% residual carcinoma) rate was 50.7%. The median OS was 6.43 years (95% Cl 3.27-12.36) for the entire cohort and 11.1 years (95% Cl 7.1-not estimable) for patients that underwent surgery. The estimated 2- and 5-year OS rates were 72% (95% CI 62-80) and 54% (95% CI 43-64) for the entire cohort and 83% (95% CI 72-91) and 66% (95% CI 53-76) for patients that underwent surgery. Pathological lesser stage (stage I/II vs. stage III/IV) (p = 0.001) and R0 resection (p = 0.019) were independently associated with longer RFS in the multivariate analysis. Conclusions: Our data show that three-drug combination is feasible without providing substantial advantage in this setting of preoperative induction chemotherapy followed by chemoradiation and surgery.