Homozygous familial hypercholesterolemia (hoFH) is caused by mutations in the low-density lipoprotein receptor gene and is characterized by severe hypercholesterolemia from birth and onset of premature cardiovascular disease (CVD) during childhood. The onset and progression of CVD using currently available testing methods in children with hoFH have not been fully characterized. A large cohort of patients with hoFH referred to our subspecialty clinic was studied. Thirty-nine patients (22 aged ≤16 years) underwent extensive cardiovascular, lipid, and genetic evaluation. Sixteen children ≤16 years without known CVD when first evaluated were followed up longitudinally for up to 8 years. CVD was clinically evident in 88% of subjects aged >16 years and 9% of those ≤16 years. Markers of atherosclerosis correlated significantly with age at which lipid-lowering treatment was initiated (abnormal coronary angiogram, abnormal aortic valve using echocardiography, and high calcium score using electron beam computed tomography; all p <0.01; abnormal carotid Doppler result; p = 0.03). Twenty of 22 children had no clinical evidence of coronary artery disease, yet 7 of these children had angiographically confirmed mild coronary artery disease (<50%) and 8 had mild to moderate aortic regurgitation using echocardiography. Of noninvasive tests, only evaluation of aortic valve regurgitation using echocardiography predicted the presence of angiographic coronary stenosis (p <0.001). During follow-up, 7 children developed progression of coronary and/or aortic valvular disease during their teenage years and 4 required surgical interventions. In conclusion, in these patients aggressive lipid-lowering treatment initiated in early childhood is warranted. Careful coronary and valvular surveillance strategies and coronary revascularization when appropriate are also warranted in this high-risk population.