A 64-yr-old man with benign monoclonal gammopathy developed recurrent episodes of severe hypoglycemia but lacked evidence of insulinoma or exogenous insulin administration. The patient's plasma was found to contain anti-insulin antibodies and large amounts of extractable insulin (1110 microU/ml), which was identified as human insulin by high-performance liquid chromatography (HPLC). The anti-insulin antibodies consisted solely of IgG and lambda-light chains. Scatchard analysis of these antibodies revealed an almost straight-line relationship, with markedly low affinity and high capacity. An immune complex made of 125I-labeled insulin and the patient's antibodies emerged in a molecular-sieve HPLC as almost a single peak, suggesting a homogeneous antibody population. In addition, the patient's M protein was separately shown to be the IgG and lambda-light-chain type. We suggest that the insulin autoantibodies responsible for the spontaneous hypoglycemia in this patient are monoclonal and of M protein origin.