Stimulating anti-TSH receptor antibodies (TSAb) mimic TSH in the induction of refractoriness in cultured thyroid cells; TSAb and TSH desensitize one another. We investigated whether blocking anti-TSH receptor antibodies (TBkAb) have the same desensitizing effects in cultured human thyroid cells. Prolonged exposure of cells (20 h) to TBkAb followed by antigen-antibody dissociation by an acid wash step was required to induce refractoriness to subsequent stimulation of cAMP accumulation with TSH and TSAb. Cycloheximide prevented this desensitization effect. The cAMP response to forskolin was not reduced in cells pretreated by TBkAb and was increased in cells desensitized by TSH or TSAb. The pattern of the TSH dose-response curves suggested that desensitization by TSH or TSAb involved only a postreceptor mechanism but both receptor and postreceptor phenomena in the case of TBkAb. In conclusion, like TSH or TSAb, TBkAb may induce a homologous desensitization in human thyroid cells which is not mediated by cAMP.