To study the effects of methylprednisolone on immune mechanisms in the absence of other immunosuppressive agents or immunologically mediated diseases, we gave 17 normal adult male volunteers 96 mg of methylprednisolone daily for 3-5 days and compared results with 12 untreated controls who were studied simultaneously, 86% of treated volunteers had significant decreases in the concentrations of serum IgG. 2-4 wk after methylprednisolone, the treated volunteers had a mean decrease in IgG of 22% compared with a decrease of only 1% in untreated controls. Likewise, significant decreases in IgA concentration occurred in 43% of treated volunteers, whereas significant decreases in IgM occurred in only 14%. The lowest immunoglobulin levels occurred during the 2nd wk after a 3 day course of methylprednisolone and during the 3rd wk after a 5 day course of drug. Slightly decreased plasma concentration of [(125)I]IgG was seen in six of seven volunteers who received a 5 day course but in only one of four who received a 3 day course of drug. However, an increase in the rate of plasma clearance of IgG occurred only during the treatment period itself. During the period when the serum concentration of IgG was falling, the specific activity of IgG in the serum was relatively higher in treated men than in controls indicating decreased entry of newly synthesized IgG into the circulation. These findings suggest that a short course of methylprednisolone treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and to decreased synthesis during and for a variable time after drug administration.