We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60mg/Kg, sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with Pyr-apelin-13 (Pyr-AP13, 200µg/Kg/day, ip) or a similar volume of saline, resulting in 4 groups: SHAM (n=11); SHAM-AP (n=11); MCT (n=16) and MCT-AP (n=13). On day 25, right (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. Compared to SHAM, MCT group presented a significant increase of RV mass (166±38%), cardiomyocyte's diameter (40±10%), myocardial fibrosis (95±20%), peak systolic pressure (99±22%), dP/dtmax (74±24%), dP/dtmin (73±19%) and time-constant- (55±16%). In these animals, RV expression of apelin (-73±10%) and its receptor APJ (-61±20%) was downregulated, whereas mRNA expression of BNP (9606±713%), angiotensinogen (191±147%), ET-1 (RV: 497±156%; LV: 799±309%), plasmatic levels of apelin (104±48%) and angiotensin 1-7 (ANG-(1-7), 161±151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target as it significantly attenuates RV overload and PH-induced neurohumoral activation.