We demonstrate the utility of partitioning the spiritual well-being (SpWB) construct into spiritual and religious components using results from a study of the relationship of existential well-being to health-related quality of life (HRQOL) in a sample of 237 cancer survivors. Existential and religious well-being were measured using the FACIT-Sp-12 and HRQOL was measured using the mental and physical component scores of the SF-12. In hierarchical linear regression analyses, existential well-being fully mediated religious well-being's effect on HRQOL and explained unique variance in both the mental and physical HRQOL domains, controlling for demographic, disease, and psychosocial variables previously shown to impact HRQOL. Religious well-being was not predictive of HRQOL.