Abstract Background/Introduction Transthoracic two-dimensional echocardiography (2DE) remains the backbone for non-invasive assessment of the right ventricle (RV) size and function. However, calculation of RV end-diastolic (RVEDV), end-systolic volume (RVESV) and ejection fraction (RVEF) cannot be performed using 2DE due to the complex RV shape (1), whereas currently used, respective 2DE indices lack diagnostic accuracy. Deep learning (DL) may be able to assist in developing new 2DE methods for RV quantification. Purpose To develop a novel DL-based 2DE method for quantitative evaluation of RV size and function without geometric assumptions. Methods 50 adult patients underwent 2DE and CMR within 30 days as part of routine cardiac care between 6/2020 – 9/2021 at a medical center. We excluded patients with prior cardiac surgery of the RV, tricuspid or pulmonic valve repair or replacement, complex congenital heart disease, more than small pericardial effusion, cardiac tamponade, atrial fibrillation at the time of either study, severe RV dysfunction or inadequate imaging quality. End-diastolic and end-systolic areas derived from planimetry of 8 2DE RV views, along with patient age and gender, were to used to train and test a DL algorithm, namely the Feature-Tokenizer and Transformer (Figure 1) in order to predict the corresponding, CMR-derived, RVEDV or RVESV, and subsequently calculate RVEF. We used 5-fold cross-validation for training and evaluation. We assessed the relative importance of each 2DE view using gain metric-powered explainability analysis and subsequently performed a sensitivity analysis to identify optimal combinations of views. Variability analysis was performed for a random subcohort of 10 patients. Results Median age was 51 (interquartile range 32-62) and 42% were women. Mean RVEDV, RVESV and RVEF) by CMR were 163±70ml, 82±42ml and 51±8% respectively. Six patients (12%) had RV dilatation and 9 (18%) had RV dysfunction when using published CMR criteria. Explainability analysis showed that the 3 most important views were parasternal long axis (PLAX) (relative feature importance [RFI] = 0.197), 4-chamber (RFI=0.145) and parasternal short axis at the base (PSAX-base) (RFI=0.112). The 3-view combination of PLAX, 4-chamber and PSAX-base achieved high accuracy when compared to CMR (R2=0.964, absolute percentage error [APE]=8.09±12.07% for RV volumes and APE=9.86±10.68% for RVEF). Good (intraclass correlation coefficient [ICC]>0.75) to excellent (ICC>0.90) intra- and interobserver variability was found for these 3 views. Conclusions We propose an innovative, clinically applicable DL-based 2DE method for quantification of RV size and function that requires manual RV planimetry of 3 views, namely 4-chamber, PLAX and PSAX-base (Figure 2). This method may revolutionize 2DE RV assessment. Further studies with largest number of patients and wider range of RV size and function are needed to validate this method.Deep learning architectureGraphical abstract