Human C-reactive protein (hCRP) is a major acute-phase reactant in man. The regulation of the hCRP gene in transgenic mice is similar to that in humans. To map DNA regions required for the correct regulation of the hCRP gene, several constructs have been generated, and their expression in transgenic mice has been analyzed. Constructs lacking DNA regions surrounding the poly(A) site of the gene are not expressed either before or after induction in transgenic mice. Minimal regions 540 base pairs upstream and 1.2 kilobases downstream of the hCRP gene are sufficient for liver-specific expression. Extended 5'- and 3'-flanking regions are required to silence the expression prior to induction. Our findings demonstrate that regulatory sequences shown to confer inducible expression of the hCRP gene in hepatoma cell lines are insufficient in transgenic mice.