This study examined the relationship between spirituality/religiousness and quality of life and the moderating effect of comorbid illness in a sample of 308 long-term cancer survivors who had received an initial primary cancer diagnosis of breast, prostate, colorectal, and Hodgkin's disease at least 5 prior to the beginning of the study. In addition to the self-report measures assessing the variable of interest, participants completed a set of socio-demographic items and several questions related to their cancer treatment at entry into the study (T1) and at a second assessment 12 months later (T2). Results showed that each spirituality/religiousness and comorbidity was significantly related to various aspects of quality of life at both time points of assessment. More specifically, spirituality/religiousness was significantly associated with greater cancer benefits, enhanced general quality of life, lower sexual dysfunction, but unexpectedly, greater family-related distress at T1. Similarly, comorbidity significantly related to more financial problems, worries about appearance, and pain at both time points. Greater comorbidity was also significantly associated with more sexual dysfunction and lower general quality of life at T1. Findings also provided supported for the moderating role of comorbidity on various domains of quality of life both concurrently (i.e., family-related distress and appearance concerns) and prospectively (i.e., family-related distress and pain). In some cases, the direction of the interaction effect was in the predicted direction such that greater spirituality/religiousness related to lower family-related distress (prospectively) and more appearance concerns (concurrently at T2) among survivors with a new comorbidity, for example. In other cases, the direction of the interaction was contrary to expectations, such that higher spirituality/religiousness was associated with greater family-related distress (concurrently at T1) and more pain (prospectively) among the group of survivors with greater comorbidity. Possible explanations for the apparently inconsistent findings are offered as well as recommendations for future research.