Male guinea pigs weighing 300 to 400 g were given a daily subcutaneous injection of 5, 20 or 100 mg/kg body weight of cortisone acetate. Measurement of serum cortisol demonstrated sustained blood levels proportional to the dose. All nine components of the classical complement pathway were measured by functional assay. At 5 mg/kg/day significant (p < 0.05) changes noted were a 20 and 51% elevation of the CH50 and C1 titers, respectively. C4, C2, and C3–9 complex were higher than saline treated controls but these increases were not statistically significant. High dose glucocorticoid therapy produced a marked depression in the titer of a number of components. At 20 mg/kg/day C4 and C8 titers were most strongly affected although all components except C1 and C9 were at least 15% lower than controls. At 100 mg/kg the titers of all components except C1 and C9 were markedly depressed. During the first 2 weeks of therapy there was a progressive fall in complement followed by stabilization at these lower levels. On discontinuation of therapy 2 weeks were required before the levels of these components returned to normal. Albumin and globulin levels, hematocrit, spleen size, and percentage of weight gain were unaltered by cortisone therapy. There was no effect on hemolytic complement levels by adding hydrocortisone in vitro to guinea pig serum in comparable doses to those obtained in vivo. Thus, altered catabolic and/or synthetic rates are responsible for the cortisone-induced changes in serum complement.