In poorly differentiated thyroid cancer, molecular characteristics are reported to be lost such as to cause insensitivity of the tumor to radiometabolic therapy. Considerable work is in progress to identify compounds that redifferentiate thyroid cancer cells. The present study evaluates the action of valproic acid, a potent anticonvulsant recently reported to inhibit histone deaceytlase, on cultured thyroid cancer cells. N-PA (poorly differentiated) and ARO (anaplastic) cells were treated with increasing valproic acid concentrations.; expression of mRNA and cell localization pattern for the Na+/I- symporter (NIS), as well as 125I uptake, were evaluated before and after treatment. Valproic acid induced NIS gene expression, NIS membrane localization and iodide accumulation in N-PA cells; it was effective at clinically-safe doses in the therapeutic range. In ARO cells, only induction of NIS mRNA was observed, and was not followed by any change in iodide uptake. Valproic acid is thus effective at restoring the ability of N-PA cells to accumulate iodide and its use in clinical trials may be recommended.