Acute heart failure (AHF) is a life-threatening condition with poor prognosis. Gender differences have been increasingly recognized in diverse cardiovascular diseases. The present study aimed to evaluate gender-specific prognostic markers of all-cause death in AHF patients based on a prospective 18-month follow-up study. Data were collected from 419 patients with AHF hospitalization who were followed up for 18 months using all-cause death as primary endpoint. The mean age of all patients was 60.9 ± 15.7 years old, 277 were males, and 142 were females. Females had higher rate of valvular heart disease (37.3%) and atrial fibrillation (45.8%) but lower rate of cardiomyopathy (30.3%) than males in this cohort. Based on multiple COX stepwise regression and ROC curve analysis, diastolic blood pressure (DBP), serum sodium, serum creatinine, and pulmonary artery systolic pressure (PASP) were identified as independent predictors of all-cause death in male AHF patients, while systolic blood pressure (SBP), serum aspartate transaminase (AST), serum creatinine, and serum D-dimer as independent predictors in females. Kaplan-Meier analysis showed a higher probability of all-cause death over time in male AHF patients with DBP ≤ 77 mmHg, serum sodium ≤ 138.5 mM, serum creatinine ≥ 126.2 μM, or PASP ≥ 52 mmHg, and in female AHF patients with SBP ≤ 129 mmHg, serum AST > 29.3 U/L, serum creatinine ≥ 102.7 μM, or serum D-dimer ≥ 1.76 mg/L. In conclusion, these data provide novel insights into gender differences in prognostic markers of outcomes of AHF patients.