BACKGROUND Emerging evidence suggests that neuroadaptations to alcohol may result from chronic alcohol consumption-induced expression changes of microRNAs (miRNAs) and their target genes. Studies with animal or cell culture models have demonstrated that ethanol exposure leads to miRNA expression alterations. However, there is limited information on miRNA expression in the brains of subjects with alcohol use disorders (AUDs). The present study aimed to analyze expression changes of miRNAs and their target genes in postmortem prefrontal cortex (PFC) of AUD subjects. METHODS Genome-wide miRNA and mRNA expression was examined in postmortem PFC of 23 European Australia AUD cases and 23 matched controls using the Illumina HumanHT-12 v4 Expression BeadChip array, which targets 43,270 coding transcripts and 3,961 non-coding transcripts (including 574 miRNA transcripts). Multiple linear regression analysis and permutation test were performed to identify differentially expressed miRNAs and their target mRNAs. Target gene prediction, Gene Set Enrichment Analysis (GESA), and DAVID functional annotation clustering analysis were applied to identify AUD-associated gene sets and biological modules. RESULTS Two miRNAs and 787 coding genes were differentially expressed in the PFC of AUD cases [miR-130a (downregulated): Ppermutation=0.023, miR-604 (upregulated): Ppermutation=0.019, coding genes: 1.6×10-5≤Ppermutation≤0.05; but all P values did not survive multiple-testing correction]. GESA showed that the 202 predicted target genes of miR-130a were highly enriched in differentially expressed genes (Pnominal<0.001), but not the 116 predicted target genes of miR-604 (Pnominal=0.404). DAVID functional clustering further revealed that the hub target genes (e.g., ITPR2 and ATP1A2) of miRNA130a were mainly responsible for regulating ion channel function. CONCLUSION This study provides evidence that downregulation of miR-130a may lead to altered expression of a number of genes in the PFC of AUD subjects. Further studies are warranted to confirm these findings in replication samples and other reward-related brain regions.