Background: A cancer diagnosis and subsequent treatment can cause significant psychosocial distress, including fear about the end of life (EoL). Although distress is common, it often goes unrecognized due to the challenge of routine psychosocial distress screening. This study sought to determine patient characteristics associated with EoL-related distress. Methods: A validated psychosocial distress screening tool (SupportScreen) was administered to patients prior to treatment at an NCI-designated cancer center between 2009-2017. Fear about EoL was measured on a 5-point Likert scale with scores of ≥3 indicating “high” distress. Multivariable logistic regression was used to test the association between fear of Eol and patients’ characteristics (age, sex, education, household income, survey language, race/ethnicity, and cancer diagnoses). Pairwise comparisons were run for cancer types and p-values were adjusted. Results: A total of 4,198 patients with cancer were included. Of these, 21.5% reported high distress from fear about EoL. Most patients were women (61%) and non-Latino white (60%). The average age was 59.9 years (SD = 13.9). About 29% of the participants had household income < $40,000. The most common cancers in this sample were breast (22%), hematological (15%), gastrointestinal (14%) and gynecological (13%). Adjusted analyses showed that being a woman (OR = 1.30, p < 0.042), taking the survey in Spanish (OR = 1.71, p = 0.020) and having a household income < $40,000 (OR = 1.80, p < 0.001) were all associated with high distress for EoL. Among cancer types, lung cancer (versus breast, digestive, gynecological, hematological, and prostate cancers) was significantly linked to high distress (p-values < 0.05). Conversely, older age (OR = 0.99, p = 0.009) was associated with low distress. Conclusions: In this study, we identified patient clinical and demographic characteristics associated with high levels of distress due to fear of EoL. Patients who have lower household income, limited English proficiency, are younger, and female, as well as patients with lung cancer, may benefit from targeted screening for EoL distress, to facilitate early identification and tailored supportive care assistance.