This study determined if altered vascular prostacyclin (PGI₂) and/or thromboxane (TxA₂) production with reduced PO₂ contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZR) vs. lean Zucker rats (LZR). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in PO₂ under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism, nitric oxide synthase, and alleviating elevated vascular oxidant stress. Production of arachidonic acid metabolites was assessed using pooled arteries from OZR and LZR in response to reduced PO₂. Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZR vs. LZR. NOS inhibition had no significant impact on hypoxic dilation in either strain. COX inhibition dramatically reduced hypoxic dilation in LZR and abolished responses in OZR. Treating arterioles from OZR with PEG-SOD improved hypoxic dilation, and this improvement was entirely COX-dependent. Vascular PGI₂ production with reduced oxygen tension was similar between strains, although TxA₂ production was increased in OZR; a difference that was attenuated by treatment of vessels from OZR with PEG-SOD. Both blockade of PGH₂/TxA₂ receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZR may be an increased vascular production of TxA₂, which competes against the vasodilator influences of PGI₂. These results also suggest that the elevated vascular oxidant stress inherent in the metabolic syndrome may contribute to the increased vascular TxA₂ production and may blunt vascular sensitivity to PGI₂.