Background/: CCl₄ cirrhotic rat liver exhibits a hyperesponse to the ₁- adrenergic agonist, methoxamine (Mtx) that is associated with enhanced thromboxane A2 (TXA₂) production and is abrogated by Indomethacin. Aim/Methods: To further elucidate the molecular mechanisms involved in the hyperresponse to vasoconstrictors, portal perfusion pressure (PP) dose-response curves to Mtx were performed in CCl₄ cirrhotic rats livers after preincubation with vehicle, the cyclooxygenase-1 (COX-1) selective inhibitor SC-560 and the cyclooxygenase-2 (COX-2) selective inhibitor SC-236. TXA₂ production was determined in samples of the perfusate. COX-1 expression was analyzed and quantified in hepatocytes, Kupffer cells, sinusoidal endothelial cells (SEC) and hepatic stellate cells (HSC) isolated from control and cirrhotic rat livers by double immunofluorescence staining with specific markers for each population using flow cytometry or Western blot. Results: COX-1 protein levels were not significantly increased in cirrhotic livers, but COX-2 protein expression was increased. COX-1 inhibition, but not COX-2, significantly attenuated the response to Mtx, and prevented the increased production of TXA₂. Cirrhotic livers showed an increased expression of COX-1 in SEC and reduced expression in HSC in comparison to control livers, while COX-1 was similarly distributed in Kupffer cells. Conclusion: Despite abundant hepatic COX-2 expression, the increased response to Mtx of cirrhotic livers is mainly dependent of COX-1. Up-regulation of COX-1 in cirrhotic SEC may be responsible for the hyperesponse to Mtx.