An inappropriate molar ratio of circulating insulin to glucagon is frequently associated with the metabolic alterations accompanying diabetes mellitus. Plasma immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) levels were determined and the IRG:IRI ratio calculated at various intervals in overt diabetes in genetically diabetic (db/db) and in streptozotocin-treated mice. Plasma IRI levels in genetic mutants are elevated at nine weeks of age, but are comparable to values found in lean littermates by 21 weeks. The presence of a prevailing hyperglucagonemia is established for the first time in the intact db/db mice. Streptozotocin diabetics are found to have characteristically low plasma IRI and high plasma IRG values. The hormonal imbalance present in these two experimental animal models is accentuated when the data are expressed as the IRG:IRI ratio, which is seen to increase with the progression of diabetes. 1 This work was supported by an NIH Training Grant 5T01-GM-326-16 (11-944P) to S.B.S. and by Grants RR0542 (11-E043C; 11-E104D) from USPHS General Research Support Branch and from the Research Foundation of State University of New York (11-7124A) to C.A.B.