Background: Despite advances in cancer disease prevention, diagnosis, and treatment patients with cancer suffer from a variety of sometimes severe physical and psychological symptoms regardless of the stage of the disease. The aim is to determine the relationship of antecedent factors and mediating variables to the quality of life (QOL) of patients with cancer. Materials and Methods: The study included 341 patients with cancer and symptoms. Data collection used the Cancer Symptom Scale, State-Trait Anxiety Inventory, Centers for Epidemiologic Study-Depression, Cancer Behavior Inventory, Multidimensional Quality of Life Index, and a Demographic Form. Results: A multiple regression equation containing all the variables explained 68% of the variance in QOL. Overall four variables accounted for the majority of the total variance: anxiety, depression, self-efficacy, and symptom severity. Three of these variables were mediating variables. Of the antecedent factors symptom severity had a significant indirect effect on QOL through the mediating variables. Symptom severity also had direct effect on QOL. Conclusion: Data indicate that anxiety, depression, and self-efficacy play major roles in determining the perception of QOL of cancer patients. These mediating variables either buffered or enhanced the impact of the antecedent factors of symptom severity on QOL. Nursing interventions should focus on enhancing self-efficacy. Nurses can use health promoting programs to assist patients who are physically impaired. Further research should be aimed at identifying other influential variables, with the ultimate goal of developing interventions to aid patients in their efforts to maintain their QOL while living with cancer.