We have previously shown that administration of glucosamine after trauma-hemorrhage (TH) improved cardiac output and organ perfusion, and this was associated with increased levels of O-linked N-acetylglucosamine (O-GlcNAc) on proteins in the heart and brain. An alternative means of increasing O-GlcNAc levels is by inhibition of O-linked N-acetylglucosaminidase, which catalyzes the removal of N-acetylglucosamine from proteins, with O-(2-acetamido-2-deoxy-d- glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc). The goal of this study, therefore, was to determine whether PUGNAc administration after TH also improves recovery of organ perfusion and function. Fasted male rats were bled to and maintained at a mean arterial blood pressure of 40 mmHg for 90 min, followed by fluid resuscitation. Intravenous administration of PUGNAc (200 μmol/kg body weight) 30 min after the onset of resuscitation significantly improved cardiac output compared with the vehicle controls (12.3 ± 1.3 mL/min per 100 g body weight vs. 25.5 ± 2.0 mL/min per 100 g body weight; P < 0.05), decreased total peripheral resistance (6.6 ± 0.8 mmHg/mL per minute per 100 g body weight vs. 3.7 ± 0.3 mmHg/mL per minute per 100 g body weight; P < 0.05), and increased perfusion of critical organ systems, including the kidney and liver, determined at 2 h after the end of resuscitation. Treatment with PUGNAc also attenuated the TH-induced increase in plasma IL-6 levels (864 ± 112 pg/mL vs. 392 ± 188 pg/mL; P < 0.05) and TNF-α levels (216 ± 21 pg/mL vs. 94 ± 11 pg/mL; P < 0.05) and significantly increased O-GlcNAc levels in the heart, liver, and kidney. Thus, PUGNAc, like glucosamine, improves cardiac function and organ perfusion and reduced the level of circulating IL-6 and TNF-α after TH. The similar effects of glucosamine and PUGNAc support the notion that the protection associated with both interventions is mediated via increased protein O-GlcNAc levels. ©2007The Shock Society.