The liver has the unique capability to regenerate from injury due to compensatory proliferation of remnant hepatocytes. For this process, hepatocytes leave their quiescent state and re-enter the cell cycle until the original liver mass is restored. Cyclin-dependent kinase 2 (Cdk2) is an important cell cycle mediator driving S-phase initiation and cell cycle progression via complex formation with E- and A-type cyclins, respectively. The aim of the study was to evaluate the role of Cdk2 for liver regeneration. Hepatocyte-specific Cdk2 knockout mice (Cdk2Δhepa) and wild type (WT) controls were subjected to partial hepatectomy (PH) and analyzed for liver regeneration and expression of cell cycle mediators. Surprisingly, Cdk2Δhepa mice showed normal liver regeneration and hepatocyte proliferation. We thus analyzed the mechanisms leading to compensation of Cdk2 deficiency. Cdk2Δhepa mice showed stronger basal expression and accelerated up-regulation of cyclin D1 (CcnD1), cyclin E1 (CcnE1) and accelerated CcnD1-mediated kinase activity following PH. However, no compensatory CcnE/Cdk kinase activity could be detected in Cdk2Δhepa mice hinting at a kinase-independent function of CcnE1 during liver regeneration. A proposed and in part kinase-independent function of CcnE is the involvement in pre-replication complex formation via interaction with minichromosome maintenance (MCM) proteins. In time course experiments with mitogenic activated, primary Cdk2-/- hepatocytes we detected an earlier onset of MCM2 expression and demonstrated co-localization with CcnE1 at chromatin pointing to a premature pre-replication complex formation in Cdk2-/- hepatocytes potentially triggering DNA replication without Cdk2.In summary we demonstrate that Cdk2 is dispensable for liver regeneration and conclude that Cdk2-deficiency is compensated by CcnD1-related kinase activity and kinase-independent functions of CcnE1 at the pre-replicative complex.