Abstract: Background: Recent studies have illuminated the diversity of roles for microRNAs in cellular, developmental, and pathophysiological processes. The study of microRNAs in human liver tissue promises to clarify the therapeutic and diagnostic value of this important regulatory mechanism of gene expression. Results: We conducted genome-wide profiling of microRNA expression in liver and performed an integrative analysis with previously collected genotype and transcriptome data. We report here that the Very Important Pharmacogenes (VIP Genes), comprising of genes of particular relevance for pharmacogenomics, are under substantial microRNA regulatory effect in the liver. We set out to elucidate the genetic basis of microRNA expression variation in liver and mapped microRNA expression to genomic loci as microRNA expression quantitative trait loci (miR-eQTLs). We identified common variants that attain genome-wide significant association (p < 10[-10]) with microRNA expression. We also found that the miR-eQTLs are significantly more likely to predict mRNA levels at a range of p-value thresholds than a random set of allele frequency matched SNPs, showing the functional effect of these loci on the transcriptome. Finally, we show that a large number of miR-eQTLs overlap with SNPs reproducibly associated with complex traits from the NHGRI repository of published genome-wide association studies as well as variants from a comprehensive catalog of manually curated pharmacogenetic associations. Conclusion: Our study provides important insights into the genomic architecture of gene regulation in a vital human organ, with important implications for our understanding of disease pathogenesis, therapeutic outcome, and other complex human phenotypes.