Phosphodiesterase (PDE) and calmodulin (CaM) activities were studied in soluble fractions of normal and Graves' thyroid tissue. Normal and Graves' thyroid tissues were obtained at thyroid surgery. PDE activities were assayed with cAMP and cGMP as substrates. CaM activity was measured as the ability to activate bovine thyroid CaM-dependent PDE. cAMP and cGMP PDE activities were increased 1.5- and 2.2-fold above normal in Graves' thyroid, respectively. The major cause of the increase in enzyme activities was their higher Ca+2 dependence. CaM activity also was 1.6-fold increased in Graves' thyroid, although it probably does not contribute to the increase in the Ca+2 dependence of PDE activities because of its relative sufficiency vs. PDE in normal thyroid. Three forms of cAMP and cGMP PDE activities were eluted from Sephadex G-200 columns, with mol wt of 280,000, 140,000, and 80,000-100,000, respectively. The first peak had little or no CaM dependence, the second peak had moderate or dominant CaM dependence, and the third peak revealed weak or dominant CaM dependence. The increase in the CaM-dependent form of the third peak of PDE activity in Graves' thyroid tissue may explain the increase in Ca+2 dependence of PDE activities.