Background: Leukemia is the most common malignancy in young adults that has a life-threatening nature which increases the patients' spiritual needs, leading to emergence of spiritual crises. However, evidences indicate that spiritual needs of patients and their spiritual well-being are not emphasized among health care personnel. According to the cultural, religious and social backgrounds as well as contradictory findings in studies, this study intends to determine the effects of a spiritual-based intervention on spiritual well-being of patients with leukemia.Methods: This randomized clinical trial was conducted at Sayyed-Al-Shohada Hospital (Isfahan, Iran) in 2012-2013. We randomly divided 64 adult patients with leukemia into experimental and control groups. In the experimental group, a spiritualbased intervention that included supportive presence and support for religious rituals was implemented for three days. Both groups completed the Palutzian and Ellison Spiritual Well-being Questionnaire before and after the intervention. Data was analyzed using ANCOVA, chi-square, the Mann-Whitney U-test, and paired and independent t-tests in SPSS (Version 18, SPSS Inc., Chicago, IL).Results: There was a significant difference in the scores of the experimental group before and after the intervention (P<0.001). This difference was absent in the control group. According to ANCOVA results, the mean score of spiritual well-being after spiritual-based intervention in the experimental group was more than the mean score of spiritual well-being in the control group. This result was statistically significant (P<0.001, F=63.303)Conclusion: Our spiritual-based intervention promoted the spiritual well-being of patients with leukemia. Therefore, in cases of refractory diseases such as leukemia, nurses should apply a holistic care approach with emphasis on spirituality-based intervention.