With most cardiovascular disease risk factors, endothelium-dependent dilation of skeletal muscle resistance arterioles is compromised, although with hypercholesterolemia, impairments to reactivity are not consistently observed. Using apolipoprotein E (ApoE) and low density lipoprotein receptor (LDLR) gene deletion male mouse models of hypercholesterolemia at 20 weeks of age, the hypothesis tested in this study was that arteriolar dilation would be maintained due to an increased stimulus-induced production of dilator metabolites via cyclooxygenase and cytochrome P450 epoxygenase pathways. Arterioles from both strains demonstrated mild reductions in dilation to hypoxia and acetylcholine versus responses in C57/Bl/6J (C57) controls. However, while inhibition of nitric oxide synthase (NOS) attenuated dilation in arterioles from C57, this effect was absent in ApoE or LDLR. In contrast, cyclooxygenase-dependent portions of dilator reactivity were maintained across the three strains. Notably, while combined NOS and cyclooxygenase inhibition abolished arteriolar responses to hypoxia and acetylcholine in C57, significant reactivity remained in ApoE and LDLR. While inhibition of cytochrome P450 -hydroxylase and epoxygenases had no effect on this residual reactivity in ApoE and LDLR, inhibition of 12/15 lipoxygenase with nordihydroguaiaretic acid abolished the residual reactivity. With both hypoxic and methacholine challenges, arteries from ApoE and LDLR demonstrated an increased production of both 12(S)- and 15(S)-HETE, end products of arachidonic acid metabolism via 12/15 lipoxygenase, a response that was not present in C57. These results suggest that with development of hypercholesterolemia, mechanisms contributing to dilator reactivity in skeletal muscle arterioles are modified such that net reactivity to endothelium-dependent stimuli is largely intact.