We undertook a study to compare the safety of intravenous (i.v.) versus oral hydration to prevent nephrotoxicity associated with the use of foscarnet for induction therapy of cytomegalovirus (CMV) infection in HIV-infected persons. Patients, given foscarnet at a dose of 90 mg/kg every 12 h, were randomized to receive either i.v. or oral hydration. Thirty-seven patients were given i.v. hydration and 44 were given oral hydration. Median duration of therapy for both groups was 17 days. There was no difference between the 2 groups in either serious adverse events or rise of creatinine to ≥2.0 mg/dl. However, serum creatinine, while generally remained within normal limits, increased more in patients who received oral hydration after 10 days of therapy (significant only by slope analysis, P <0.05). Although i.v. hydration provided better protection against nephrotoxicity, oral hydration was relatively safe and convenient provided that creatinine clearance (CrCl) is monitored closely.