Microvascular dysfunction predicts adverse cardiovascular events despite absence of large vessel disease. A shift in the mediator of flow‐mediated dilatation (FMD) from nitric oxide (NO) to mitochondrial‐derived hydrogen peroxide (H2O2) occurs in arterioles from patients with coronary artery disease (CAD). The underlying mechanisms governing this shift are not completely defined. Lipid phosphate phosphatase 3 (LPP3) is a transmembrane protein that dephosphorylates lysophosphatidic acid, a bioactive lipid, causing a receptor‐mediated increase in reactive oxygen species. A single nucleotide loss‐of‐function polymorphism in the gene coding for LPP3 (rs17114036) is associated with elevated risk for CAD, independent of traditional risk factors. LPP3 is suppressed by miR‐92a, which is elevated in the circulation of patients with CAD. Repression of LPP3 increases vascular inflammation and atherosclerosis in animal models. We investigated the role of LPP3 and miR‐92a as a mechanism for microvascular dysfunction in CAD. We hypothesized that modulation of LPP3 is critically involved in the disease‐associated shift in mediator of FMD. LPP3 protein expression was reduced in left ventricle tissue from CAD relative to non‐CAD patients (P = 0.004), with mRNA expression unchanged (P = 0.96). Reducing LPP3 expression (non‐CAD) caused a shift from NO to H2O2 (% maximal dilatation: Control 78.1 ± 11.4% vs. Peg‐Cat 30.0 ± 11.2%; P < 0.0001). miR‐92a is elevated in CAD arterioles (fold change: 1.9 ± 0.01 P = 0.04), while inhibition of miR‐92a restored NO‐mediated FMD (CAD), and enhancing miR‐92a expression (non‐CAD) elicited H2O2‐mediated dilatation (P < 0.0001). Our data suggests LPP3 is crucial in the disease‐associated switch in the mediator of FMD. Key points: Lipid phosphate phosphatase 3 (LPP3) expression is reduced in heart tissue patients with coronary artery disease (CAD).Loss of LPP3 in CAD is associated with an increase in the LPP3 inhibitor, miR‐92a.Inhibition of LPP3 in the microvasculature of healthy patients mimics the CAD flow‐mediated dilatation (FMD) phenotype.Inhibition of miR‐92a restores nitric oxide‐mediated FMD in the microvasculature of CAD patients. [ABSTRACT FROM AUTHOR]