Fibromyalgia is a chronic pain disorder characterized by uncertainty in etiology, symptomatology, diagnosis, treatment, and outcome. The high level of illness uncertainty that results from fibromyalgia is a risk factor for maladjustment to illness. A cross-sectional survey design was used to examine the relationships among illness uncertainty, helplessness, and subjective well-being in 138 women with fibromyalgia. Multiple regression analyses were conducted to examine a predictive model for mediation. We found illness uncertainty is negatively associated with subjective well-being and that helplessness strongly influences the impact of illness uncertainty on subjective well-being in women with fibromyalgia.