In uncomplicated VSD, the flow of blood is from the left ventricle through the VSD traversing the right ventricle and into the pulmonary artery. This results in a volume overload of the pulmonary circulation, the left atrium, and the left ventricle. A systolic murmur is created by blood flowing through the VSD (for restrictive VSDs) or through the pulmonary valve (for unrestrictive VSDs). If the patient develops pulmonary vascular obstructive disease, this direction of flow of blood can reverse such that desaturated blood from the right ventricle will traverse the VSD into the left ventricle and out the aorta. These patients may exhibit cyanosis.

The clinical presentation of patients with VSD depends primarily upon the size of the VSD and, to a much lesser extent, upon the type of VSD. If the VSD is as large as the aorta, it is considered to be a large VSD. More than the size of the VSD, however, determines the size of the left-to-right shunt. If the VSD itself is unrestrictive to blood flow, then the downstream resistance of the right ventricular outflow tract or the pulmonary microcirculation will determine the volume of pulmonary blood flow. The type of VSD may influence the clinical presentation. For example, a patient with a supracristal VSD may present primarily with aortic valve insufficiency.