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OBJECTIVE To examine different expression profiles of plasma exosomal microRNA (miRNA) in polycystic ovary syndrome (PCOS) patients and controls, and their potential roles in PCOS pathogenesis. DESIGN Experimental study. SETTING Center for reproductive medicine. PATIENT(S) Seventy-five PCOS patients and 75 age-matched controls. INTERVENTION(S) Plasma exosomes miRNAs sequenced from 15 PCOS patients and 15 controls. MAIN OUTCOME MEASURE(S) Plasma exosomal miRNA expression and the correlation between PCOS phenotypes and miRNA expression. RESULT(S) The sequenced plasma exosomes miRNAs were further determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in a larger cohort, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Correlation analysis and receiver operating characteristic (ROC) curve analysis were used to determine the association between PCOS phenotypes and miRNA expression. The miRNA sequencing revealed 34 exosomal miRNAs were differentially expressed between PCOS patients and controls. Via qRT-PCR, five differentially expressed miRNAs (miR-126-3p, miR-146a-5p, miR-20b-5p, miR-106a-5p, and miR-18a-3p) were identified. The GO and KEGG analyses predicted their target functions included axon guidance, mitogen-activated protein kinase (MAPK) signaling, endocytosis, circadian rhythms, and cancer pathways. The expression of these miRNAs correlated with menstrual cycle, antral follicle count, hormone level, and combined yielded a ROC curve area of 0.781 in discriminating PCOS patients from the controls. CONCLUSION(S) Differential expression of plasma exosomal miRNAs may confer a risk of PCOS and may be helpful in distinguishing PCOS patients from controls. Certain miRNA expression may associated to the disease progression, which could help in an epigenetic understanding of the pathophysiology of PCOS.