Bisphosphonates currently are used in treatment of osteoporosis and metastatic bone disease to inhibit bone resorption. It also has been shown that bisphosphonates have direct anti-cancer activity in chronic myeloma leukemia cells through inhibition of prenylation of the small GTPases Ras and Rap1a. Our lab has reported synthesis of dialkyl bisphosphonates in which the substituents were isoprenoid chains with varying lengths (Bioorg Med Chem, 2006, 14:4130-6). These isoprenoid bisphosphonates caused a decrease in intracellular geranylgeranyl pyrophosphate (GGPP) leading to diminished protein geranylgeranylation. For this study, we hypothesized that addition of pivaloyloxymethyl (POM) groups to a selection of these isoprenoid bisphosphonates would result in increased biological activity. Synthesis of the POM-modified digeranyl bisphosphonate (1) and other POM bisphosphonates will be described. It was found that both the POM and salt forms of the isoprenoid bisphosphonates had varying activity towards inhibition of geranylgeranylation. In some cases, both the salt and POM are active, but bioactivity was significantly enhanced by addition of the POM groups. Some compounds that were previously shown to be inactive as salts are highly potent as the POM derivatives. This data suggests that prodrug modifications of these bisphosphonates merit further study.