To explore whether lithium-induced hypothyroidism is related to an exacerbation of underlying autoimmune processes such as thyroiditis, the authors comprehensively assessed thyroid function in 16 manic-depressive patients. Each of the three patients who showed detectable titers of thyroid microsomal antibodies before treatment manifested a marked increase in antibody titer from 4 to 12 months after lithium treatment was begun. Thus, lithium-induced thyroid dysfunction may not only involve direct effects on the thyroid itself but also involve exacerbation of an underlying indolent autoimmune thyroiditis, possibly by causing shifts in T lymphocyte subpopulations.