Background: Ampullary adenocarcinoma (AC) is a rare clinical entity representing only 0.2% of gastrointestinal malignancies. While outcomes are superior compared to other hepatobiliary cancers, mortality remains high. There is limited data to guide clinical decisions regarding adjuvant therapy, largely extrapolated from other hepatobiliary cancers. We evaluated treatment strategies and variables associated with survival in patients with AC. Methods: We retrospectively reviewed 54 consecutive patients with pathologically proven AC between January 2012 and August of 2015. Demographic data, adverse prognostic features and adjuvant treatment patterns were examined using a cox univariate hazard model for predictors of overall survival (OS). There were 5 patients who had metastatic disease on presentation who were included for markers of poor prognosis but excluded from treatment analysis. Results: The average age was 64.7 years with 50% male. Treatment strategy included 40.8% surgery alone, 44.9% adjuvant chemotherapy (CT) and surgery, 14.2% chemoradiation (CRT) and surgery while only 1 patient did not have surgery. Open surgical whipple (n = 28) was most frequent followed by laparoscopic whipple (n = 18) and endoscopic resection (n = 2). The two most common chemotherapeutic agents were single agent gemcitabine (74%) and capecitabine plus oxaliplatin. (7%). At time of last follow-up, 20 (37%) patients had died with a median follow-up of 16.8 months (range 1.9 to 47.4). Older age (HR [95% CI]: 1.05 [1.02, 1.09]; p = 0.002), Stage III (6.75 [1.40, 32.53]; p = 0.017), Stage IV (32.44 [32.44, 216.92]; p < 0.001), N stage 1 (8.52 [2.44, 29.67]; p = 0.014), lymphovascular invasion (LVI) (4.80 [1.54, 15.00]; p = 0.007), and peri-neural invasion (PNI) (3.835 [1.197, 12.29]; p = 0.024) were all associated with poor OS. There was no difference in OS between histologic subtype, surgery type, adjuvant CT or CRT. Conclusions: There was no difference in OS between adjuvant CT or CRT, or between surgical modalities. Despite being administered more frequently in patients with adverse prognostic features including LVI, PNI and advanced stage, adjuvant CT or CRT was equivalent to no adjuvant therapy.