Sixteen patients with Reye syndrome had diminished concentration of serum complement proteins and/or hemolytic activity in the earliest blood sample. All 12 studied with hemolytic methods had significantly reduced Cl activity; total hemolytic complement activity was reduced in only three. Low Cl activity was accompanied by equivalent reduction of Cls in 11 of 12 patients; Clq was less than normal in only two of 12. Decreased levels of at least one other classical pathway complement component hemolytic activity or protein concentration were found in 13 patients, whereas factor B of the alternate complement pathway was normal or elevated in the ten patients studied. The consistent reduction of Cls protein concentration in Reye syndrome suggests that early metabolic abnormalities regularly affect the production or catabolism of this protein. Although normal serum Clq concentration in the majority of these patients does not support an immune pathogenesis, decreased Clq, C4, and C2 in three patients does suggest that immune mechanisms may be responsible for the serum complement abnormalities in this latter group of patients.