Considerable attention has focused on relationships between religious or spiritual coping and health outcomes among cancer patients. However, few studies have differentiated among discrete dimensions of religious coping, and there have been surprisingly few prospective investigations. Negative or conflicted aspects of religious coping, in particular, represent a compelling area for investigation. This prospective study examined negative religious coping, positive religious coping, and general religious orientation among 94 myeloma patients undergoing autologous stem cell transplantation. Participants were assessed during stem cell collection, and again in the immediate aftermath of transplantation, when risks for morbidity are most elevated. Outcomes included Brief Symptom Inventory anxiety and depression and Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMI) scales. Negative religious coping at baseline predicted worse post-transplant anxiety, depression, emotional well-being, and transplant-related concerns, after controlling for outcome scores at baseline and other significant covariates. Post-transplant physical well-being was predicted by an interaction between baseline positive and negative religious coping. Results suggest that religious struggle may contribute to adverse changes in health outcomes for transplant patients, and highlight the importance of negative or strained religious responses to illness.