Abstract We investigated the effects of HMG-CoA reductase inhibitors, so-called statins, on 5,6,7,8-tctrahydrobioptcrin (BH 4 ) metabolism in human umbilical vein endothelial cells (HUVEC). The mRNA of GTP cyclohydrolase I (GTPCH), as well as cNOS, was upregulated in HUVEC treated with cerivastatin. This increase was time- and dose-dependent. Fluvastatin was also observed to enhance GTPCH and eNOS mRNA levels. In parallel with this observation, cerivastatin increased intracellular BH 4 . Cerivastatin increased the stability of eNOS mRNA. However, it did not alter the stability of GTPCH mRNA but increased GTPCH gene transcription as shown by nuclear run-on assays. Preteatment of HUVEC with the selective GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, caused a decrease in intracellular BH 4 and decreased citrulline formation following stimulation with ionomycin. Furthermore, the potentiating effect of cerivasatin was decreased by limiting the cellular availability of BH 4 . In addition to augmenting eNOS expression, statins potentiate GTPCH gene expression and BH 4 synthesis, thereby increasing NO production and preventing relative shortages of BH 4