Zinc-a 2 -glycoprotein (Zna 2 gp) is widely distributed in body¯uids and epithelia. Its expression in strati®ed epithelia increases with differentiation. We previously showed that Zn a 2 gp has ribonuclease activity, and that squamous tumor cells grown on a matrix of Zna 2 gp were growth-inhibited. Here we demonstrate, both by adding Zna 2 gp to the culture medium and, more unequivocally, by stably transfecting SiHa cells with Zna 2 gp cDNA, that the introduction of Zna 2 gp into SiHa tumor cells reduces proliferation. In response to Zna 2 gp, we ®nd an accumulation of the cell population in G 2 /M by¯ow cytometry, paralleling the reduction of proliferation. In order to distinguish growth inhibition by cell cycle arrest from that produced by apoptosis or differentiation, we examine by RT-PCR how Zna 2 gp affects the expression of genes commonly used as markers of these properties. No changes are observed for PCNA, p53, c-myc, or bcl-2. Only cdc2 expression responds to Zna 2 gp, with a reduction of up to over a factor of two. Cdc2 is the only cyclin-dependent kinase regulating the G 2 /M transition without redundancy and is required as a rate-limiting step in the cell cycle. Its increased expression has been directly linked to increased proliferation and decreased differentiation of advanced tumors; conversely, its downregulation by Zna 2 gp might hinder tumor progression.