Hemoglobin-based oxygen carrier-201 (HBOC) was developed as a resuscitative fluid but concerns exist over potentially adverse vasoconstriction. This study evaluated whether concurrent IV (intra venous) N-acetyl-L-cysteine (NAC) or hyaluronic acid (HA) would attenuate HBOC-associated vasoconstriction, assessed by systemic blood pressures and cerebral pial microvasculature, when administered to healthy, anesthetized rats. Rats (8-9/group) received a 30 min infusion of 3 ml/kg HBOC, HBOC plus 600 mg/kg NAC (HBOC/NAC), HBOC plus 1.5 mg/kg HA (HBOC/HA) or 3 ml/kg Albumin. Mean (MAP) and systolic (SBP) blood pressures, blood chemistries and cerebral pial vessel diameters were measured at baseline, end of infusion, and intermittently for an additional 90 min. HBOC caused immediate and sustained increases in SBP and MAP (35.3 ± 3.6 and 29.1 ± 2.5 mm Hg peak increases above baseline, respectively; mean ± SEM) and immediate but progressive vasoconstriction (11 µm maximum reduction) in medium-sized (50-100 µm) pial arterioles. When NAC was co-administered, blood pressure changes were attenuated and vessel changes were abolished. Similar trends were noted with co-administration of HA but were not statistically different from HBOC-alone. Small-sized (< 50 µm) pial vessels and blood parameters showed no differences from baseline or among groups. No adverse clinical signs were observed. We demonstrated that it is possible for adjuvant drugs to reduce the vasoconstriction associated with HBOC-201. Coinfusion of the anti-oxidant NAC mitigated HBOC-201-associated increases in blood pressures and vasoconstriction in medium-sized cerebral pial vessels. The drag-reducing polymer HA may be more effective at a higher dose as a similar but non-significant trend was observed.