Mutations at conserved sites within the ligand-binding LDL-A modules of the LDL receptor cause the genetic disease familial hypercholesterolemia (FH), and several of these FH mutations in modules five and six prevent the isolated single modules from folding properly to a nativelike three-dimensional structure. Because LDL-A modules occur as a series of contiguous repeats in the LDLR and related proteins, we investigated the impact of two FH mutations in LDL-A module five (D203G and D206E) and two mutations in module six (E219K and D245E) in the context of the covalently connected module five-six pair. HPLC chromatography of the products formed under conditions that efficiently refold the native module five-six pair demonstrate that, for each mutation, a folding defect persists in the module pair. NMR spectroscopy and calcium affinity measurements of the ensemble of misfolded products demonstrate that the unaltered module of each pair can fold to its native structure regardless of the range of misfolded conformations adopted by its mutated neighbor. These findings lend additional support to a model in which individual LDL-A modules of the LDL receptor act as independent structural elements.