Squamous cell carcinomas of the head and neck (HNSCC) and of the cervix (CC) are particularly sensitive to the apoptotic effects of lovastatin in vitro. In this Phase I study, the safety and maximum related dose (MTD) of lovastatin was evaluated in these specific clinical settings. This was a Phase I open-label study to determine the recommended Phase II dose (RPTD) of lovastatin in advanced HNSCC or CC. This study involved a dose and duration escalation of lovastatin starting at 5/mg/kg/day x 2 weeks, every 21 days, until the MTD was reached. Plasma samples were collected for pharmacokinetic analysis. All 26 patients enrolled were evaluable. Dose-limiting toxicity (DLT) consisting of reversible muscle toxicity was seen at 10 mg/kg/day x 14 days. Toxicity may be related to relative renal insufficiency. The MTD was determined to be 7.5 mg/kg/day x 21 days, every 28 days. The low lipid levels experienced on study did not translate into adverse events. Biologically relevant plasma lovastatin levels were obtained. No objective responses were seen but the median survival of patients on study was 7.5 months (mean 9.2 +/- 1.5 months). Stable disease (SD) for more than 3 months was seen in 23% of patients. One patient achieved SD and clinical benefit for 14 months on study and a further 23 months off treatment. The disease stabilisation rate of 23% seen in these end-stage patients is encouraging. We conclude that the administration of lovastatin at 7.5 mg/kg/day for 21 consecutive days on a 28-day schedule is well tolerated in patients with good renal function and warrants further clinical evaluation.