ObjectiveThe role of health knowledge and empowerment in explaining behavioral and health outcomes was treated in depth in the literature, but the combined effect of these constructs has been somehow neglected. This study presents an empirical, a priori, cross-sectional evaluation of the differential effects of health knowledge and empowerment on patients’ self-management and health outcomes. MethodsThis study relies on a cross-sectional design involving a total of 209 Fibromyalgia patients. Structural Equation Modeling techniques were employed to analyze the model relationships. ResultsKnowledge and three empowerment dimensions were found to positively impact health outcomes. However, these relationships were not mediated by self-management. Self-management, operationalized in terms of physical exercise and drug intake, was found to be a strong predictor of health outcomes. ConclusionDespite the lack of support for the mediating role of self-management, a strong impact of knowledge and empowerment over health outcomes was observed. Theories of health literacy and empowerment may benefit from this result by integrating both dimensions in an overall model of behavioral and health outcomes change. Practice implicationsResults from this study suggest that health interventions targeted to chronic patients should focus simultaneously on knowledge and empowerment, rather than favoring one of these individual constructs.