Pharmacological enhancement of cholinergic activities by administering physostigmine is known to induce protective effects. It is unclear, however, whether the impact of physostigmine on inflammation and acetylcholine metabolism is related to different types of surgical intervention or to anesthesia alone. To determine this, rats were subjected to partial liver resection (PLR) or sham surgery. A control group only received anesthesia. Half of each treatment group received a single intraoperative dose of physostigmine; the others received placebo. Acetylcholine esterase (ACHE) activity and IL1ß and acetylcholine (ACH) concentrations were determined. Both PLR and sham operation induced a time‐dependent increase in plasma concentration of IL1ß (3.9 and 4.8‐fold) as compared to rats that received anesthesia alone. In rat brain, IL1ß had increased by about twofold after surgery as compared to controls. Blood ACHE was transiently decreased after surgery. Brain ACHE activity increased 1.3‐fold (p=0.014) only after PLR; consequently, the cerebral ACH concentration was significantly reduced. Physostigmine administration significantly reduced IL1ß and ACHE levels. Cerebral ACH concentration was markedly increased from 543.9±121.5 (placebo) to 653.5±93.3 ng mg‐1 protein (p<0.001) after administering physostigmine. We conclude that a single dose of physostigmine intraoperatively had a sustained anti‐inflammatory effect up to 120 min after injection that was especially pronounced under the conditions of PLR surgery. In addition to its protective peripheral action, physostigmine exerts neuroprotective action by increasing levels of the neurotransmitter ACH. This article is protected by copyright. All rights reserved.