alpha1-Proteinase inhibitor is a serpin and can inhibit most serine proteinases. The cornea is one of several extrahepatic tissues that synthesizes this inhibitor. In the presence of retinol, corneal alpha1-proteinase inhibitor levels were increased 3.8-fold. The maximal response was achieved 2 h after the addition of retinol (1 microM final concentration) to the culture medium. A similar increase in alpha1-proteinase inhibitor was observed with retinaldehyde (1 nM final concentration). Concentrations of alpha1-proteinase inhibitor in other tested cells (Hep G2, CaCo 2, MCF-7, monocytes and macrophages) remained unchanged in the presence of retinol. Retinoic acid did not affect alpha1-proteinase inhibitor levels in the cornea or the other cells tested. The acute-phase cytokine, interleukin-6, increased alpha1-proteinase inhibitor levels in all tested tissues/cells except the cornea. These results demonstrate that alpha1-proteinase inhibitor levels are controlled differently in the cornea compared with other tissues/cells. alpha1-Proteinase inhibitor is the first protein identified whose levels are regulated by a mechanism supported by retinol and retinaldehyde but not retinoic acid.