Although genome-wide association (GWA) studies have provided valuable insights into the genetic architecture of human disease, they have elucidated relatively little of the heritability of complex traits. A significant part of the missing heritability might be explained by rare combinations of common SNPs. We hypothesized that epistasis among 15 genes (148 SNPs) involved in lipoprotein metabolism would influence HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) levels. Using SNPwinter software with the various epistatic models, we identified 58 association signals with HDL-C levels for SNPs in eleven genes and 118 associations with LDL-C for SNPs in fourteen genes. These associations were discovered in the urban Ansan cohort (n = 4,102) and replicated in a rural cohort (n = 3,434), the Ansung. We found replicated associations with new genes (SOAT1, APOB, HMGCR, and FDFT1 for HDL-C, and SOAT1, FDFT1, LPL, SQLE, ABCA1, LRP1, SCARB1, and PLTP for LDL-C), in addition to those (CETP, LIPC, LPL, ABCA1, PLTP, SCARB1, and LRP1 for HDL-C, and CETP, LIPC, LDLR, APOB, CYP7A1, and HMGCR for LDL-C) identified by GWA studies, through investigating pairwise interactions between candidate genes of biological and clinical importance. Interestingly, we found that some genes were more likely to be involved in epistatic interactions (ABCA1 and LIPC for HDL-C, and ABCA1, SCARB1, and LIPC for LDL-C).