OBJECTIVE Ischemia/reperfusion injury (IRI) remains a clinical challenge. We tested the hypothesis that fluid therapy using hydroxyethyl starch (HES) 130/0.4 during the early phase of IRI in rat liver decreases markers of hepatic injury. METHODS We induced liver IRI in three groups of rats anesthetized with ketamine and chlorpromazine by means of 60 min of segmental hepatic ischemia followed by 120 min of reperfusion. At the onset of reperfusion, Group 1 (IRI + HES; n = 12) was given 13 mL.kg(-1) of HES; Group 2 (IRI + HS; n = 12) received the same volume of 7.5% saline (HS), and Group 3 (IRI-only; n = 12) received no fluid. Three other groups of 12 animals each were sham-operated and received the same fluid as the test groups. We euthanized the animals after three hours, drew blood for alanine aminotransferase (ALT) quantification, and took ischemic liver samples for histomorphological study. RESULTS Serum ALT activity was greater in all of the IRI groups than in the sham-operated animals. The ALT activity was 1,081 +/- 575 IU.L(-1) in IRI + HES Group 1; 2,363 +/- 1,839 IU.L(-1) in IRI + HS Group 2; and 2,866 +/- 2,491 IU.L(-1) in IRI-only Group 3. There was a statistically significant difference between the IRI + HES and the IRI-only groups (P = 0.001), but not between the IRI + HS and the IRI-only groups (P > 0.05). Likewise, histological scores were greater in all IRI groups compared with the sham-operated animals. Scores were higher in the IRI-only group (median 3.5) than in the groups receiving fluid (IRI + HES median 2; IRI + HS median 3). The difference between IRI + HES and IRI-only was statistically significant (P = 0.008) but not so between IRI + HS and IRI-only (P > 0.05). CONCLUSIONS Giving HES 130/0.4 attenuates rat liver IRI compared with no fluid, while giving HS does not. This suggests a role for HES in hepatoprotection associated with liver IRI.