The safety and efficacy of total dose infusion (TDI) of iron dextran has been well documented. In 40% of treated patients, an arthralgia-myalgia syndrome develops. The purpose of this randomized, double-blind, prospective study was to investigate whether intravenous (IV) administration of methylprednisolone (MP) prevents this complication. Sixty-five patients, 34 women and 31 men, ages 36 to 80 years, received either normal saline before and after TDI (group 1), 125 mg IV MP before and saline after TDI (group 2), or 125 mg IV MP before and after TDI (group 3). Patients were observed for 72 hours and reactions were recorded and graded according to severity. Fifty-eight percent of group 1 patients, 33% of group 2, and 26% of group 3 had reactions to TDI. The severity of reactions (minimal, mild, and moderate, respectively) was as follows: group 1-6, 6, and 2; group 2-1, 5, and 0; group 3-5, 1, and 0. Data were analyzed by the two-sided Fisher's exact test using 95% confidence intervals with the approximation of Woolf. These data demonstrate that administration of MP before and after TDI reduces the frequency and severity of the arthralgia-myalgia syndrome. We conclude that 125 mg IV MP should be given routinely before and after TDI of iron dextran.