Membrane differential filtration (cascade filtration) is an apheresis technique by which atherogenic lipoproteins can be eliminated from plasma on the basis of particle size. In this study, we aim to discuss the efficacy of low-density lipoprotein (LDL) apheresis performed by providing alternative vascular routes in two siblings with familial hypercholesterolemia who did not respond to medical treatment and diet. Of the two siblings, one was nine years old and the other one was three-and-a-half years old. Of the total of 78 apheresis processes performed, 24 were done via a permanent subclavian catheter, 36 were done via a subsequently provided arteriovenous fistula, and 18 were done via an arteriovenous graft. We observed a mean reduction in the plasma levels of total cholesterol (61.6%), LDL cholesterol (65.5%), and high-density lipoprotein cholesterol (38.6%). We noted that cascade filtration apheresis was effective in decreasing the LDL cholesterol in plasma, and no serious complications were noted. The success of the apheresis program depends on well-functioning blood access. An arteriovenous fistula may be the best route for the long-term treatment of familial hypercholesterolemia, which requires complication-free apheresis treatments.