Background: Gastrectomy with complete tumor removal and negative margins (R0 resection) is the most effective treatment for gastric cancer. Potential benefits of neoadjuvant therapy for locally advanced gastric cancer include tumor downstaging and an increased R0 resection rate. Potential disadvantages include increased surgical complications. This study was designed to examine the effect of CPT-11 based neoadjuvant chemotherapy on surgical morbidity and mortality. Methods: We reviewed the medical records of 105 patients who underwent gastrectomy for adenocarcinoma of the stomach from October 1998 through July 2002. 34 patients with locally advanced gastric cancer (T3 or N+) were prospectively followed on a Phase II neoadjuvant chemotherapy protocol consisting of 2 cycles of CPT-11 (75mg/m2) combined with Cisplatin (25mg/m2) followed by surgery. Demographic, clinical, morbidity and mortality data were compared by Chi-square analysis for these 34 patients (CHEMO) versus 71 patients undergoing gastrectomy without neoadjuvant chemotherapy during the same time period (SURG). Results: There were no significant differences between the two groups with respect to age, sex, race, tumor location, extent of resection, or AJCC stage. R0 resection rate was 86% in the CHEMO patients with pathologic downstaging demonstrated in 59% as compared to preoperative clinical staging. There were 2 (6%) post-operative deaths in the CHEMO group vs. 3 (4%) in the SURG group (p=ns). Twelve of 34 CHEMO patients (35%) had at least one complication compared to 29 of 71 SURG patients (41%, p=ns). There were 9 minor complications in 6 (18%) CHEMO patients vs. 22 in 16 (23%) SURG patients (p=ns). Wound and urinary tract infections were the most common minor complications. There were 12 major complications in 7 (21%) CHEMO patients vs. 40 in 22 (31%) SURG patients (p=ns). Cardiac, pneumonia and prolonged ileus were the most common major complications. Seven patients required re-operation, 3 CHEMO and 4 SURG (p=ns). Post-operative length of stay was not significantly different between the groups(8 days). Conclusion: CPT-11 based neoadjuvant chemotherapy for gastric cancer can be delivered safely, can result in tumor downstaging, and does not cause increased postoperative morbidity or mortality. Concerns of increased postoperative complications following gastrectomy should not hinder the use of CPT-11 based neoadjuvant chemotherapy for patients with locally advanced gastric cancer.