HCF is a mammalian nuclear protein that undergoes proteolytic processing and is required for cell proliferation. During productive herpes simplex virus (HSV) infection, the viral transactivator VP16 associates with HCF to initiate HSV gene transcription. Here, we show that the worm Caenorhabditis elegans possesses a functional homolog of mammalian HCF that can associate with and activate the viral protein VP16. The pattern of sequence conservation, however, is uneven. Sequences required for mammalian HCF processing are not present in C. elegans HCF. Furthermore, not all elements of mammalian HCF that are required for promoting cell proliferation are conserved. Nevertheless, unexpectedly, C. elegans HCF can promote mammalian cell proliferation because a region of HCF that is conserved can promote mammalian cell proliferation better than its human counterpart. These results suggest that HCF possesses a highly conserved role in metazoan cell proliferation which is targeted by VP16 to regulate HSV infection. The precise mechanisms, however, by which HCF functions in mammals and worms appear to differ.