C16orf35 is a highly conserved gene positioned upstream of the alpha-globins in humans and other vertebrates. The deduced protein is also highly conserved, it has no defined structural features or domains, and its function is currently unknown. Here we show that the C16orf35 protein has nuclear and cytosolic distribution, and can localize to PML nuclear bodies. The C16orf35 protein was detected in several human transformed cells lines, and studies of transient and stable overexpression indicate that increased levels of C16orf35 inhibit cell proliferation. We also find that C16orf35 interacts with human p73, and represses transcription by TAp73gamma but not by TAp73alpha. This selectivity is not due to differential interaction, since C16orf35 binds both p73 variants. Our data suggest that C16orf35 can modulate differentially the specific activities of selected p73 isoforms.