Rationale: When diagnosed with cancer, a patient has to cope with stressors such as pain, fatigue, and the experience of life-threat that can cause great distress. Spirituality may be a resource for coping with these problems, thereby reducing distress. Objective: Two questionnaire studies the first a cross-sectional (Study 1; N = 216) and the second a one-year longitudinal (Study 2; N = 383) investigated among Dutch cancer patients whether spirituality lessens the impact of pain, fatigue, and perceived life-threat on distress. Method: Data for Study 1 were gathered in 2006-2007 and for Study 2 in 2009-2010. Spirituality was measured with the Spiritual Attitude and Involvement List, which assesses six distinct but related aspects of spirituality. Linear regression analysis and marginal effect plots were applied. Results: Limited evidence appeared for the hypothesis that spirituality reduces the impact of pain, fatigue, or perceived life threat on distress. Meaningfulness and acceptance might reduce a negative impact of increases in fatigue during the rust year after the start of cancer treatment. In contrast, spirituality might enhance a negative impact of increases in perceived life threat. Conclusions: Processes of appraisal might explain the findings. Experiences of meaningfulness and acceptance might help to reappraise fatigue in a less threatening way, thereby reducing distress. Conversely, appraising the cancer as life-threatening might conflict with spiritual experiences of meaning, acceptance, and awe about life. Future studies should focus on the processes by which the various aspects of spirituality influence the adjustment of cancer patients and use other outcome variables than non-specific distress. Such studies may provide further clues as to how the spirituality of patients can be harnessed to help them adjust to a serious life event such as the occurrence of cancer.