Background: Simple transposition of the great arteries (TGA) is a cyanotic critical congenital heart defect representing a neonatal cardiovascular emergency, which requires surgery early after birth. In case of inadequate mixing between systemic and pulmonary circulations, creating an unrestrictive interatrial communication is mandatory. The aim of the present study was to identify the most important echocardiographic parameters that can predict the need for balloon atrial septostomy (BSA) in TGA neonates. Material and methods: We retrospectively reviewed the echocardiographic recordings of newborns with TGA referred to our emergency room during a 6-year period. We measured the following echocardiographic parameters: atrial septal defect (ASD) size, interatrial septum (IAS) length, peak/mean interatrial pressure gradient, transverse diameter of the left atrium (LA), and transverse diameter of the right atrium (RA). Also, the ratio between ASD/IAS, the ratio between LA/RA, the ratio between mitral/tricuspid annulus, the ASD peak gradient/ASD diameter and the ASD diameter/(LA:RA ratio) were calculated. Results: There were 37 neonates with simple TGA presented to the emergency room, split into two groups: those with BAS (n = 21) and those without BAS (n = 16). Besides significant differences between the two groups in ASD size, peak/mean interatrial pressure gradient, and LA:RA ratio, we found that ASD peak gradient/ASD diameter was significantly higher, but ASD diameter/(LA:RA ratio) was significantly lower in the group that required BAS compared with the group without BAS. Multivariate analysis showed that ASD diameter/(LA:RA ratio) was an independent predictor of septostomy requirement, with a cut-off value of 2.58. Conclusion: ASD diameter/(LA/RA ratio) is a useful echocardiographic parameter that can provide supplementary information regarding inadequate mixing and the need for BAS in neonates with TGA.