All 241 patients with an apparently benign monoclonal gammopathy who were examined at the Mayo Clinic before Jan. 1, 1971, underwent prospective follow-up for 20 to 35 years (median, 22 years). Electrophoresis and immunoelectrophoresis of serum and urine specimens were performed periodically in an effort to determine the frequency of development of multiple myeloma, primary amyloidosis, macroglobulinemia, or other lymphoproliferative diseases. At follow-up, the patients were categorized into one of four groups: group 1 (benign)--46 patients (19%) who were alive and had a benign monoclonal gammopathy; group 2--23 patients (10%) who had a serum monoclonal protein value of 3 g/dl or more but did not require chemotherapy; group 3--113 patients (47%) who died without evidence of myeloma or related disorders; and group 4-59 patients (24%) in whom multiple myeloma (39), systemic amyloidosis (8), macroglobulinemia (7), or a malignant lymphoproliferative disease (5) developed at a median of 10, 9, 8, and 10 1/2 years, respectively, after detection of the monoclonal protein. Thus, in patients with an apparently benign monoclonal gammopathy, follow-up must be continued indefinitely because multiple myeloma, amyloidosis, macroglobulinemia, or related disorders occur in approximately a fourth of them.