Homozygosity disequilibrium (HD), indicating a nonrandom pattern of sizable runs of homozygosity that deviates from a random allocation of homozygous and heterozygous genotypes in the genome, is an important phenomenon in population genomics and medical genomics. We performed the first genome-wide study investigating the roles of HD in pharmacogenomics and pharmacoepigenomics by analyzing GAW20 data. We inferred whole-genome profiles of homozygosity intensities and performed genome-wide homozygosity association analyses to identify regions of HD associated with triglyceride (TG) response to fenofibrate by using LOHAS (Loss-of-Heterozygosity Analysis Suite) software. The analysis identified a region of HD contained in MACROD2 at 20p12 to be significantly associated with TG response to fenofibrate. We also examined the common genetic component in TG and methylation responses to fenofibrate. The methylation response to fenofibrate was regarded as a methylation quantitative trait, and our methylation quantitative trait locus analysis identified a cis-acting regulation association with marginal significance between the homozygosity intensity of MACROD2 and the methylation response to fenofibrate. These findings may help delineate the genetic basis of pharmacogenomic and pharmacoepigenomic responses to fenofibrate intervention.