There is strong evidence that low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl) produced by myeloperoxidase is present in atherosclerotic lesions and can propagate inflammation. Less is known about the biological reactivity of LDL modified by hypothiocyanous acid (HOSCN), the other major oxidant produced by myeloperoxidase in vivo . We examined the role of HOCl- and HOSCN-modified LDL in the induction of endothelial dysfunction, which is characterised by decreased nitric oxide ( ● NO) formation and is a key pathway to atherosclerotic lesion development. Exposure of human coronary artery endothelial cells (HCAEC) to both HOCl- and HOSCN-LDL resulted in a greater extent of endothelial nitric oxide synthase (eNOS) uncoupling compared to control LDL, which correlated with a decrease in eNOS activity. A significant decrease in ● NO production was also seen on exposure of HCAEC to each modified LDL for 24 h, though no elevation in superoxide (O 2 ●– ) production from uncoupled eNOS was observed. We also performed studies to see if the reduced eNOS functionality is consistent with the caveolin-1-mediated down-regulation of eNOS activity. While eNOS and caveolin-1 remained colocalised in the cell, as shown by fluorescence microscopy, we did not observe any binding of eNOS and caveolin-1 in HCAEC exposed to each modified LDL. The changes in ● NO production were also independent of mRNA and protein expression of cellular adhesion molecules; ICAM-1, VCAM-1 and E-selectin, and cytokines; MCP-1 and IL-6, which remained unchanged. Together, these data provide new insights regarding the role of LDL modified by myeloperoxidase-derived oxidants, in altering endothelial function within the setting of atherosclerosis, and may have particular significance for smokers, who have elevated plasma thiocyanate, the precursor to HOSCN.