Prenatal cardiac intervention (PCI) may favorably alter the in utero course of some congenital heart defects. In our preliminary experience with PCI, fetal hemodynamic instability (FHI) characterized by bradycardia and ventricular dysfunction was common. This study evaluated the pathophysiology, management, and short-term outcomes of FHI during PCI for aortic stenosis with evolving hypoplastic left heart syndrome (HLHS), HLHS with restrictive atrial septum, pulmonary atresia with intact ventricular septum, and hydrops due to structural heart disease. From 2000 to 2006, 83 fetuses underwent PCI, with ventricular access in 63, atrial access in 17, and both in three. FHI occurred in 37 fetuses (45%). FHI was associated with transventricular PCI (all but one case of FHI; p < 0.001) and large hemopericardium (n=9; p=0.07). Prolonged FHI was associated with severe ventricular distortion during ventricular puncture (p = 0.06). FHI was treated with resuscitation medications in 31 of 37 fetuses and resolved in all 37. Five fetuses died within 1 d of PCI: four had FHI and one had a massive hemopericardium. FHI is common and clinically important during transventricular PCI and may be caused by a ventricular reflex or reduced cardiac output from cardiac distortion during ventricular puncture. Hemopericardium may be causative in a subset of fetuses.