Congenital cardiovascular anomalies associated with right-left atrial or ductal shunts must be excluded before a diagnosis of persistent fetal circulation (PFC) can be made. Despite the advent of 2-dimensional echocardiography (2-D echo), this differentiation can be difficult and may require cardiac catheterization with selective angiography. Fifteen consecutive cases were analyzed in which difficulty was encountered with this differential diagnosis, and experience with the use of cardiac auscultation, the 12-lead electrocardiogram (ECG), arterial blood gas determinations and 2-D echo, both alone and with injection of venous contrast material, is reviewed. Electrocardiographic abnormalities of ventricular axis, hypertrophy or dominance (p = 0.002) and suspicion of cardiovascular disease on 2-D echo (p = 0.011) were the most useful findings in differentiating patients with PFC from those with congenital cardiovascular abnormalities. The ECG was the most sensitive test (100% sensitivity, 90% specificity), while 2-D echo was the most specific (100% specificity, 75% sensitivity). Evidence of right-left shunting at atrial or ductal levels or both did not differentiate between the groups; both groups had evidence of such shunts. A decision tree was developed to facilitate this differential diagnosis, which uses the ECG and 2-D echo. If the ECG reveals no abnormalities of ventricular axis, dominance or hypertrophy, the 2-D echo shows no structural abnormalities, and total anomalous pulmonary venous return and coarctation/interruption of the aorta are specifically excluded, a congenital cardiovascular anomaly is effectively eliminated. We suggest that this approach can optimize the management of the cyanotic newborn with suspected PFC by eliminating the risks of cardiac catheterization and angiography without missing the diagnosis of a major structural cardiovascular anomaly.