Computational fluid dynamics (CFD) was used to identify factors influencing the accuracy of the hemispherical proximal isovelocity surface area (PISA) method in calculating the effective regurgitant orifice area (EROA) for patients with functional mitral regurgitation (FMR). Ninety-nine CFD models were constructed to investigate the impact of regurgitant orifice shape and leaflet tethering on the EROA calculation using the PISA method. The correction factors for regurgitation orifice shape (CFs) and for leaflet tethering (CFt) were derived by comparing the 2D PISA method and the actual orifice area. The correction formula was then tested in vivo via 2D transthoracic echocardiography with 3D transesophageal echocardiography of the vena contracta area (VCA) as a reference method in 62 patients with FMR. Based on the CFD simulation results, the two major factors for correcting the EROA calculation were vena contracta length (VCL) and coaptation depth (CD). The correction formula for the EROA was corrected effective regurgitant orifice area (CEROA) = EROA*CFs*CFt, where CFs = 0.59 × VCL(cm) + 0.6 × MR Vmax(cm/s)-0.63 × PISA R(cm)-1.51 and CFt = 0.4 × CD (cm) + 0.96. The correction formula was applied to FMR patients, and the bias and LOA between the CEROA and VCA (0.01 ± 0.13 cm2) were much smaller than those between the EROA and VCA (0.26 ± 0.32 cm2). The CFD-based correction formula improves the accuracy of the EROA calculation based on the hemispheric PISA method, possibly leading to more accurate and reliable data for treatment decision-making in FMR patients.