Objective: Previous studies have shown that positive and negative approaches toward religious orientation are significant coping methods in cancer patients and their relatives. However, the results of these studies are controversial as to how the religious system is being used in cancer patients and their relatives for overcoming depression and how often it is used are unclear. The aim of this study was to determine the spiritual orientation as a method of coping with depression in cancer patients and their primary caregivers. Material and Methods: A survey was conducted including a face-to-face meeting with cancer patients and only one primary caregiver of these patients. For statistical analyses, the chi-squared test, Fischer’s exact test, Wilcoxon test, and logistic regression analyses were performed. Results: A total of 123 cancer patients (group 1) and their primary relatives (group 2) were included in this study. The majority of patients in group 1 were male (n=69), married (n=81), not educated (n=69), of low economic status (n=85), and older than 65 years (n=65). Most of the participants in group 2 were female (n=74), married (n=69), educated (n=71), of low economic status (n=82), and younger than 65 years (n=64). Depression rate was 63% (n=78) in group 1 and 74% (n=91) in group 2. In group 1, positive religious coping was significant. However, in group 2, negative religious coping was leading. In stepwise multiple regression analysis, negative religious coping was a significant and independent risk factor for depression in groups 1 and 2 (odds ratio [OR]: 2.14; 95% CI, 1.41-3.11; p=0.044 for group 1 and OR: 2.48; 95% CI, 1.38-4.35 for group 2). Conclusion: The use of spiritual orientation as a coping method for depression, which is the most common psychological problem in cancer, can have a positive effect on cancer patients and their relatives.