Cardiac output (CO) monitoring is essential for the optimal management of critically ill patients. Several methods have been proposed for CO estimation based on pressure waveform analysis. Most of them depend on invasive blood pressure recording and calibrations, while they suffer from decreased accuracy under specific conditions. A new Systolic Volume Balance (SVB) method was derived from a volume balance approach on the conservation of mass ejected into and flowed out of the arterial system during systole. The formula was validated by a one-dimensional model of the systemic arterial tree. Comparisons of CO estimates between the proposed and previous methods were performed in terms of agreement and accuracy by using the “real” CO values of the model as a reference. 507 different hemodynamic cases were simulated by altering cardiac period (T), arterial compliance (C) and resistance. CO could be accurately estimated by the SVB method: CO=C·PP_ao/(T-P_sm·T_s/P_m) where PP_ao aortic pulse pressure, T_s systolic duration, P_sm mean systolic pressure and P_m mean pressure. SVB applied on aortic pressure waves did not require calibration or empirical correction for CO estimation. An empirical coefficient (k) was necessary for brachial pressure wave analysis. The difference of SVB-derived from model CO, (for brachial waves), was 0.042 L/min with 0.341 L/min SD of difference. The limits of agreement were −0.7–0.6 L/min indicating high precision. The intraclass correlation coefficient and the root mean square error between estimated and “real” CO were 0.861 and 0.041 L/min, respectively, indicating very good accuracy.