Aneurysm of the sinus of Valsalva, a rare cardiac condition, results from dilation of an aortic sinus. Sudden aneurysm rupture can trigger rapidly progressive heart failure. We discuss the case of a 57-year-old woman with situs ambiguus, isolated levocardia, and polysplenia who presented with acute-onset heart failure. Transesophageal echocardiograms revealed an aneurysm of the right coronary sinus of Valsalva that had ruptured into the right atrial cavity. The patient underwent successful surgical repair. To our knowledge, this is the first report of a sinus of Valsalva aneurysm in a patient with this combination of congenital abnormalities. We briefly review the association between congenital heart disease, situs ambiguus, and ciliary dysfunction.