The evaluation of existential distress is fraught with difficulties in so far as there is no well formulated or validated taxonomy defining the involved issues, nor any well validated quantitative tool. Based on a review of the literature we devised a semi structured interview to valuate patients’ existential concerns. The interview addressed issues including autonomy/ dependency, dignity, body image, social isolation, coping mechanisms, guilt, past disappointments, spiritual health, meaning, hope, and death/dying. The interviews lasted from 30 minutes to 2 hours. The patients’ responses were simultaneously translated into English and recorded. Despite the sensitivity of the issues addressed, patients expressed satisfaction with the interview process. The responses from 40 interviews were evaluated. Overall we found that whereas existential concerns were common, only 4 of the 40 patients manifested evidence of distress. Distress was most common among patients with poor support structures and isolated patients. The patients represented a diverse cultural spectrum within Israel, reflecting Jewish, Muslim, Christian, and traditional Middle Eastern beliefs. Such cultural and religious factors may have played a role in coping with cancer, e.g., a fatalistic belief system held by many of the orthodox Jews and Muslims as well as by some of the secular Jews of Middle Eastern descent. Other factors such as family support, personal and spiritual beliefs, and the support offered by an integrated oncology/palliative care department may have contributed to the patients’ ability to cope with existential concerns. Our findings suggest that existential concerns in patients with advanced cancer may be mitigated by a strong framework of palliative measures, good family support, effective coping strategies, and religious belief systems.