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The purpose of this paper is to present a conceptual-theoretical-empirical model addressing factors that influence the relation between parental uncertainty and health-related quality of life in children with cancer. The basic concepts identified and defined in the model include parental uncertainty, health-related quality of life, parental trait anxiety, parental depression, and perceived parental social support. The proposed relationships between the concepts are explained with explicit linkages to their empirical indicators. There is limited research in childhood cancer regarding the relation between parental uncertainty and health-related quality of life; therefore, the proposed model will help to better understand this relationship.