Upon infection of human cells, the herpes simplex virus protein VP16 associates with the endogenous cell-proliferation factor HCF. VP16 can also associate with HCFs from invertebrates, suggesting that VP16 mimics a cellular protein whose interaction with HCF has been conserved. Here, we show that VP16 mimics the human basic leucine-zipper protein LZIP, which, through association with HCF, may control cell-cycle progression. VP16 and LZIP share a tetrapeptide motif-D/EHXY-used to associate with human HCF. The LZIP-related Drosophila protein BBF-2/dCREB-A contains this HCF-binding motif, indicating that the LZIP-HCF interaction has been conserved during metazoan evolution.