This study evaluates the spiritual well-being (SpWB) in very advanced cancer patients assisted by the home palliative care program of ANT Foundation, a no-profit Italian organisation. SpWB was assessed by the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-Sp12), including Meaning, Peace, and Faith subscales. The quality-of-life (QoL) was evaluated by using the Functional Assessment of Cancer Therapy-General scale. Questionnaires were distributed to 1,055 patients and 683 were compiled and evaluable for analysis. The mean scores of FACIT-Sp12 as well as of QoL were notably lower than reference values for cancer survivors. The FACIT-Sp12 score was higher in patients with less impaired Karnofsky Performance Status, fully participating in religious rituals and living in central Italy. A high Pearson's correlation was found between QoL and FACIT-Sp12 (r = .60), Peace (r = .71) and Meaning (r = .52), while it was marginal for Faith (r = .27). The hierarchical regression analysis showed that FACIT-Sp12 is a significant predictor of QoL. The study suggests that Italian patients with advanced cancer assisted by expert multi-professional teams in the home palliative care setting have a low level of SpWB thereby highlighting the need for the integration of spiritual support as part of comprehensive cancer care.