We studied humoral immunity to human thyroglobulin (hTg) during the course of multiple myeloma (MM). In this report, we describe the anti-hTg antibody activity in the sera of patients with MM. Among 63 sera tested, 28 (44%) had IgG anti-hTg autoantibodies (aAb), 16 (25%) exhibited IgM aAb, and six (9%) had IgA anti-hTg aAb. For the majority of sera the anti-hTg autoantibody activity was associated with more than one immunoglobulin class. IgG anti-hTg antibodies were observed in 9/11 patients with IgA MM and in 19/40 patients with IgG MM. The IgM anti-hTG antibody activity was found in the sera of 11 patients with IgG MM. These results show that the anti-hTg activity in these patients is associated with residual polyclonal immunoglobulins. However, in the serum of one patient presenting a double monoclonal gammopathy (IgG and IgA lambda MM), the anti-hTg activity was carried by both the IgG lambda and the IgA lambda molecules, suggesting that in this case the activity was due to the monoclonal immunoglobulin itself. We also studied the epitopic specificity pattern of all these anti-hTg aAb. Only three sera recognized one antigenic region on hTg, suggesting that the majority of the anti-hTg aAb in MM patients were directed against antigenic regions other than those recognized by our panel of murine mAb. In conclusion, our results demonstrated that humoral immunity to hTg is maintained in MM patients. These data contrast with the well-documented suppression of immunity to foreign, especially bacterial, antigens described in MM.