•Male patients had lower self-care behaviors (ScB) than females.•Patients with high ScB had significantly increased all-cause mortality in males.•Complying with regimen was associated with decreased mortality in females.•Asking for help was associated with increased incidence of heart failure admission in males.•Adapting activities was associated with adverse outcomes in both genders. Self-care behaviors (ScB) are associated with symptoms and outcomes in patients with heart failure (HF). However, little is known about gender differences in the prognostic relevance of ScB in HF patients. We examined gender differences in ScB of HF patients regarding its prognostic associations with mortality and HF hospitalization with a reference to ScB dimensions. The European Heart Failure Self-Care Behavior Scale (EHFScBS) was used to evaluate ScB in 2233 patients with Stage C/D HF in the CHART-2 Study. Male patients (n=1583) were younger (71 vs. 73 yrs) and had lower ScB (median 33 vs. 31) (all p<0.001) than females (n=650). During the median follow-up of 2.57 years, patients with high ScB (score 12–32, n=1090), as compared with low ScB patients (score 33–60, n=1143), had significantly increased all-cause mortality in males adjusted hazard ratio (aHR) 1.44, p=0.02 but not in females (aHR 0.80, p=0.40) (p for interaction 0.02), while ScB was not significantly associated with incidence of HF hospitalization in both genders. Among the 3 dimensions in EHFScBS, complying with regimen was associated with decreased mortality in females, but not in males (p for interaction 0.003), while asking for help was related with increased incidence of HF hospitalization in males (aHR 1.34, p=0.072) but not in females (aHR 0.98, p=0.931) (p for interaction 0.048). There were gender differences in the prognostic relevance of self-care with mortality and incidence of HF hospitalization, suggesting that self-care should be implemented considering gender differences to improve prognosis.