Background: Capecitabine with oxaliplatin (CAPOX) is used in front-line management of metastatic small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC). In a prior single arm phase 2 study (n = 30), CAPOX showed an overall response rate (ORR) of 52%. The purpose of this study was to evaluate safety and activity of bevacizumab and CAPOX in this population. Methods: We conducted a single-center open-label single arm phase 2 study in patients with treatment naïve metastatic SBA and AAC between 8/2011 to 11/2014. Prior fluoropyrimidine-based adjuvant therapy was allowed if completed ≥ 52 weeks. Bevacizumab-CAPOX was administered as a 21-day cycle with capecitabine 750 mg/m² orally twice daily on days 1-14, oxaliplatin 130mg/m²intravenously on day 1 and bevacizumab 7.5mg/kg intravenously on day 1. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary objectives included ORR, overall PFS, overall survival (OS) and toxicity. Results: A total of 30 patients with median age of 63 years (range 33-78) were enrolled. Six (20%) patients had AAC and 24 (80%) had SBA (duodenal: 18). Treatment was well tolerated and most common grade 3/4 toxicities included fatigue (23%), hypertension (23%), neutropenia (30%), and diarrhea (10%). Common grade 2 toxicities included anorexia (50%), fatigue (47%), and nausea (37%). 4 patients remain on study treatment to date. In 29 evaluable patients the ORR was 48.3% (1 complete and 13 partial responses). Eleven (37.9%) patients had stable disease. The PFS at 6 months was 68% (95% CI: 52%-88%). The median PFS and median OS were 8.7 (95% CI: 6.6-13.4) and 14.98 (95% CI: 10.2-21.3) months, respectively. Comparing the current study to a subset of 25 patients with metastatic disease from our prior phase 2 CAPOX study demonstrated similar ORR, 48.3% vs. 52% (p = 0.79) and PFS 8.7m vs. 6.6m (p = 0.73). Conclusions: In patients with untreated metastatic SBA and AAC, therapy with bevacizumab and CAPOX was well-tolerated and showed efficacy comparable to published regimens. Further studies are warranted to evaluate the benefit of targeting angiogenesis in this rare tumor.