Significance The two E-type cyclins E1 and E2 are known to interact with Cdk2 and are thought to trigger cell cycle activity in carcinogenesis. However, the individual contributions of cyclin E1, cyclin E2, and Cdk2 for initiation and progression of hepatocellular carcinoma (HCC) are unknown. In the present study, we discovered that only cyclin E1—but not cyclin E2—is essential for initiation of liver cancer and requires Cdk2. Unexpectedly, advanced liver cancer progression can be mediated in presence of any E-cyclin, but in a Cdk2-independent manner. We identified the specific expression profiles of cyclin E1-dependent and cyclin E1-independent hepatoma cells. These signatures are useful for predicting patient prognosis and for developing novel cyclin E-based HCC therapies.