Introduction: Molecular biology of p38 mitogen-activated protein kinase (MAPK), has shown their specific roles under stressed conditions such as heart failure (HF) in such a way that activation of p38 MAPK is viewed as pathological and pro-apoptotic indicator. On the other, compelling evidence has accumulated indicating that apoptotic cell death play a critical role in a variety of cardiovascular diseases such as heart failure. Here, we sought to gender difference evaluation the expression level of p38 MAPK kinases in animal model of heart failure disease. Material and Methods: 50 Wistar rats were randomly divided into 4 groups: male control group, female control group (no intervention was done in these two groups), male HF group, female HF group. HF groups received 130 mg/kg isoproterenol subcutaneously for four consecutive days. On the 28th day, all samples review for assessment expression level of p38 MAPK kinases by western blotting method. Results: Results demonstrated that p38 mitogen-activated protein kinase expression regulates in a gender-dependent way.In the female heart failure group, the expression reduction of p38 MAPK kinases levels was higher than male heart failure group. Discussion and Conclusions: In the comparison between males and females in the heart failure model, a reduction in the expression of p38 MAPK kinases levels was seen in females. Since the inhibition of p38 MAPK activity is in clinical evaluation as a potential therapy to mitigate acute injury in heart failure,the identification of the gender differences expression of p38 MAPK kinases regulating suggests a plausible mechanism pathways for the progression of new therapeutic decisions about heart failure.