Background: In chronic liver injury, hepatic stellate cells (HSC) have been implicated as regulators of sinusoidal vascular tone. We studied the relative role of Ca²⁺-dependent and Ca²⁺-independent contraction pathways in HSCs and correlated these findings to in-situ perfused cirrhotic rat livers. Methods: Contraction of primary rat HSCs was studied by a stress-relaxed-collagen-lattice model. Dose-response curves to the Ca²⁺-ionophore A23187 and to the calmodulin/myosin light-chain kinase-inhibitor W-7 served to study Ca²⁺-dependent pathways. Y-27632, staurosporin and calyculin, inhibitors of respectively Rho-kinase, protein-kinase C and myosin-light chain phosphatase, were used to investigate Ca²⁺-independent pathways. Actomyosin-interaction, the common end-target, was inhibited by butanedione monoxime [BDM]. The effect of W-7, Y-27632 and staurosporin on the intrahepatic vascular resistance (IHVR) was evaluated by in-situ perfusion of normal and thioacetamide (TAA) cirrhotic rat livers stimulated with methoxamine (n=25 each). Results: In vitro, HSC contraction was shown to be actomyosin-based with a regulating role for both Ca²⁺-dependent and -independent pathways. Although the former seem important, an important auxiliary role for the latter was illustrated through their involvement in the phenomenon of "Ca²⁺-sensitization". In vivo, preincubation of cirrhotic liver with Y-27632 10^-4M and staurosporin 25nM, more than with W-7 10^-4M, significantly reduced the hyperresponsiveness to methoxamine 10^-4M by -66.8±1.3%, -52.4±2.7% and -28.7±2.8% respectively, whereas in normal liver this was significantly less: -43.1±4.2%, -40.2±4.2% and -3.8±6.3%. Conclusion: Taken together, these results suggest that HSC contraction is based on both Ca²⁺-dependent and -independent pathways, which were shown to be upregulated in the perfused cirrhotic liver, with a predominance of Ca²⁺-independent pathways.