Background: Duodenal adenocarcinomas (DA) and ampullary adenocarcinoma (AA) are rare, comprising less than 1% of all gastrointestinal cancers. Optimal treatment sequencing strategies for patients with localized DA and AA have not been prospectively validated. We analyzed the clinical outcomes of patients with localized DA and AA treated with curative intent, multimodality therapy based on treatment sequencing – upfront surgery versus neoadjuvant therapy. Methods: Our institutional database was interrogated to identify adult patients with localized DA and AA diagnosed between January 2000 to December 2019. Adjusted survival analyses were performed to compare outcomes of patients that received neoadjuvant therapy (NAT - concurrent chemo-radiation +/-induction chemotherapy) versus upfront surgery (+/- adjuvant chemotherapy). Survival time was calculated from date of diagnosis to either death (overall survival; OS) or relapse/death (relapse free survival; RFS). Log-rank test and multiple Cox proportional hazards regression were performed to compare survival between treatment groups and adjust for relevant variables. Results: We identified 79 patients – 32 (41%) with DA and 47 (59%) with AA; Median age at diagnosis was 67. Forty two patients (53%) were male. Sixty-two patients underwent surgery – 27 (43.6%) patients with DA and 35 patients (56.4%) with AA. Among patients with DA, 18 (67%) were treated with upfront surgery, while 9 (33%) were treated with NAT. Among patients with AA, 32 (91%) were treated with upfront surgery while 3 (9%) were treated with NAT. Lymph node (LN) positivity rate in DA and AA patients treated with upfront surgery was 15% and 46% respectively, compared to 50% and 0% respectively, in patients treated with NAT (p = 0.26, p > 0.99 respectively). DA patients treated with upfront surgery had a median relapse free survival (mRFS) of 3.8 years compared to 1.4 years for those treated with NAT (p = 0.370). The median overall survival m(OS) was not reached (NR) for DA patients treated with upfront surgery (4 years +) or NAT (2.6 years +) p = 0.875). AA patients treated with upfront surgery had a median RFS of 4.7 years compared to NR for patients treated with NAT (p = 0.117) while the mOS of AA patients treated with upfront surgery and NAT were 5.9 years and NR respectively (p = 0.158). Conclusions: Among DA patients, there was no difference in outcome based on sequence of treatment delivery – NAT versus upfront surgery. DA patients with more aggressive clinical phenotype were likely treated with NAT, hence similar outcomes in both groups should prompt consideration of NAT for all patients with DA. Role of NAT in AA is not clear considering the small sample size.