Mitogen activated protein kinase phosphatase-1 (MKP-1) is essential in limiting the pro-inflammatory response to lipopolysaccharide (LPS). We hypothesized that Mkp-1^-/- mice would respond to low-dose LPS with a fall in blood pressure due to augmented expression of inducible nitric oxide synthase (iNOS). To test this hypothesis, Mkp-1^-/- mice and their wild-type littermates were treated with 10 µg/kg LPS iv and mean arterial blood pressure (MAP) and exhaled NO production (exNO) were measured. Tissues were harvested for assessment of iNOS protein levels. Wild-type mice had no change in MAP or exNO during the experimental period, while Mkp-1^-/- mice had a fall (p<0.005) in MAP (79 ± 5% of baseline (BL)) and an increase (p<0.01) in exNO (266 ± 50% of BL) after 150 minutes. Tissue levels of iNOS were greater in Mkp-1^-/- mice than in wild-type mice. In additional experiments, 60 minutes after LPS-treatment Mkp-1^-/- and wild type mice were given N-nitro-L-arginine (L-NAME) or aminoguanidine and MAP and exNO monitored for 90 minutes. Treatment with L-NAME prevented the LPS-induced increase in exNO and decrease in MAP but resulted in decreased exNO and elevated MAP in wild-type mice. While aminoguanidine prevented the increase in exNO and the fall in MAP caused by LPS in Mkp-1^-/- mice, without significantly effecting MAP or exNO in wild-type mice. These results demonstrate that deficiency of MKP-1 results in an exaggerated hypotensive response to LPS mediated by augmented iNOS expression. We speculate that defects in the Mkp-1 gene may increase susceptibility for the development of septic shock.