Background: The diagnosis of hepatopancreaticobiliary (HPB) cancers can cause patients significant distress. Psychological distress has been shown to negatively impact cancer treatment, recovery, and ultimately, survival. Multiple factors may place patients at increased risk for psychological distress. Identification of factors placing patients at high risk for distress will enable care teams to pre-emptively intervene to improve the course of cancer care. Herein, we investigate the association of biopsychosocial factors with psychological distress of patients with HPB malignancies. Methods: A validated forty-eight item electronic distress screen was administered to new patients in the medical and surgical oncology clinics of a large cancer center from 2009 to 2015. Responses were recorded on a five-point Likert scale from 1, indicating no problem, to 5 indicating a very severe problem. Univariate and multivariate logistic regression analyses were performed to analyze factors that impacted the psychological distress status of patients. Results: A total of 1027 patients participated in biopsychosocial screening at a single institution from 2009-2015 of which 324 (31.5%) were HPB malignancies. The median age at screening was 65. Forty-eight percent of patients were female and 61% were Caucasian. Thirty-six percent of patients had at least a college degree. On univariate analysis, BMI ≥25 (OR 0.41, 95%CI 0.19–0.90, p = 0.03), male gender (OR 0.61, 95%CI 0.38–0.97, p = 0.03), and tobacco use (OR 5.17, 95%CI 1.35–19.70, p = 0.02) were significantly associated with an increased level of overall psychological distress. However, age, race, income, non-English primary language, and level of education were not associated with increased psychological distress. On multivariate analysis, BMI ≥25, gender and tobacco use all remained significantly associated with increased psychological distress, fearfulness and anxiety (p < 0.05). Conclusion: This study demonstrates that it is feasible to identify HPB cancer patients at high risk for psychological distress. HPB patients with a BMI ≥25, male gender, and tobacco users are more likely to experience this distress. Identifying these patients will allow for early intervention and potentially improved cancer recovery and survival.