Abstract In patients with pulmonary hypertension (PH) right ventricular (RV) function is a well-recognized determinant of clinical outcome, including cardiac death. Data regarding the prognostic value of comorbidities in patients with PH are scarce. Purpose. To identify predictors of cardiac death and all-cause mortality on mid-term follow-up in PH patients receiving specific vasodilator therapy. Methods. Sixty-eight patients (40 ± 16 years, 51 women) with PH (12 with idiopathic pulmonary arterial hypertension-PAH, 32 with congenital heart disease, 10 ith connective tissue disease, 7 with chronic thromboembolic PH and 7 with other forms of PAH) treated with pulmonary vasodilators were studied. Clinical parameters (NYHA class, 6-minutes walking distance, 6MWD), biological (hemoglobin, B-type natriuretic peptide-BNP), and echocardiographic parameters of RV function (TAPSE, tissue-Doppler imaging-derived free-RV wall S- and e’-wave, RV fractional area change (FAC), Tei index, I/H, RV isovolumic acceleration-IVA) and cardiac index were assessed. RV global longitudinal strain (RV-GLS) was measured from the apical 4-chamber view as the average of 3 (free-wall) and 6 (free-wall and interventricular septum) segments by 2D speckle-tracking echocardiography. Parameters of pulmonary artery stiffness (PAS) were assessed: pulsatility, capacitance, elastic modulus, dynamic compliance. Two endpoints were defined: cardiac death and all-cause mortality. Results. PH patients were followed-up for 35 months (4-81). Comorbidities were identified in 15 patients (non-cardiac surgery, anemia, chronic kidney disease, neoplasia, respiratory infections). During follow-up, 20 patients died, 14 deaths being cardiac deaths. At univariable analysis, the following parameters correlated with all-cause mortality: age (51 ± 14 in deceased patients vs 36 ± 15 years in surviving patients, p < 0.001), 6MWD (262 ± 171 vs 369 ± 155 m, p = 0.015), FAC (30 ± 9 vs 38 ± 8%, p < 0.001), 6 segments RV-GLS (-12.3 ± 5.1 vs -15.1 ± 4.5%, p = 0.025), S-RV (9.9 ± 2.2 vs 11.4 ±2.3 cm/s, p = 0.016), TAPSE (16.3 ± 3.3 vs 18.6 ± 3.5 mm, p = 0.014), right atrial (RA) area (30.6 ± 13.1 vs 21.2 ± 8.8 cm2, p = 0.001) hemoglobin (12.9 ± 2.6 vs 15.2 ± 3.0 g/dl, p = 0.004) and BNP levels (lnBNP, 5.8 ± 1.3 vs 4.1 ± 1.4, p < 0.001), presence of comorbidities (10 vs 5, p = 0.001). At multivariable analysis, only comorbidities (p = 0.05) and FAC (p = 0.07) seemed to independently predict all-cause mortality. Predictors of cardiac death at univariate analysis were age, RV function parameters, RA area, PA capacitance (1.02 ± 0.56 vs 1.48 ± 0.80 ml/mmHg, p = 0.05) and cardiac index (2.48 ± 0.64 vs 3.31 ± 1.34 l/min/m2, p = 0.03) but only age (p = 0.03) and cardiac index (0.06) emerged as independent predictors of cardiac death. Conclusions: In PH patients, RV function and comorbidities predict all-cause mortality, while age and cardiac index are independent determinants of cardiac death. Identifying and properly treating associated pathologies could impact survival in this setting.