Identifying risk factors for psychological distress in patients with cancer may help providers more efficiently screen, identify, and manage distress. This article presents predictors of psychological distress in a large heterogeneous sample of cancer patients. In total, 836 patients were enrolled in a large randomized control trial and completed computerized psychosocial assessments Mental Health Assessment and Dynamic Referral for Oncology. Multivariate regressions examined predictors of distress and interest in mental health services. Final models suggest that psychological distress was related to six variables, and interest in mental health services was related to previous history of mental health counseling, total number of cancer-related symptoms, and race/ethnicity. Results may be used to identify high-risk patients who may benefit from proactive psychosocial interventions.