In patients with heart failure, worsening of signs and symptoms and depression can affect hospitalization and also each other, resulting in synergistic effects on hospitalizations. A patient's sex may play a role in these effects. To determine the effects of fatigue and depression on all-cause hospitalization rates in the total sample and in subgroups of men and women. A secondary analysis was done of data collected January 1, 2010, through December 31, 2012 (N = 582; mean age, 63.2 years [SD, 14.4]). Data were collected on fatigue, depression, sample characteristics, vital signs, results of laboratory tests, medications, and frequency of hospitalization. Patients were categorized into 4 groups on the basis of the International Classification of Diseases, Ninth Revision: no fatigue or depression, fatigue only, depression only, and both fatigue and depression. General linear regression was used to analyze the data. In both the total sample and the subgroups, the number of hospitalizations in patients with both fatigue and depression was greater than the number in patients without either symptom. Among women, the number of hospitalizations in the fatigue-only group and in the depression-only group was greater than that in the group with neither symptom. In men, the number of hospitalizations in the fatigue-only group was greater than that in the group without either symptom. Fatigue and depression do not have synergistic effects on hospitalization, but men and women differ in the effects of these symptoms on hospitalization.