Technetium-99m-sestamibi (MIBI) is a radionuclide tracer taken up by different malignant tumors. A total of 88 MIBI scans were carried out in 20 individuals with monoclonal gammopathy of unknown significance (MGUS) and 10 patients during follow-up for other cancers. Of these 58 MIBI scans were carried out in 46 myeloma patients: 15 at diagnosis, 14 during conventional chemotherapy, and 29 following high-dose sequential therapy and autologous peripheral blood progenitor support. A positive MIBI scan was exhibited by lof 10 with non-myeloma cancers and 2 of 20 with MGUS. In contrast, all stage II and III multiple myelomas (MM) were positive at diagnosis. Therefore, the sensitivity of the MIBI scan at diagnosis was 100%, whereas the specificity in this cohort was 93%. Four different MIBI patterns could be distinguished in MM patients: physiological, focal, diffuse, and extramedullary uptakes. In comparison to conventional skeletal radiographs, MIBI scans recognized a higher number of myeloma lesions at diagnosis. MIBI scans remained positive in all patients during conventional chemotherapy, and there was a direct correlation between MIBI result and clinical outcome of patients following high-dose therapy. Eighteen patients had a negative MIBI scan: 9 were in complete remission (CR), 8 in partial remission (PR), and 1 had progressive disease. Eleven patients showed lesions on the MIBI scan: 4 were in PR, 5 had progressive disease, 1 had a minimal response, and only 1 was in CR. A diffuse MIBI pattern reflected a higher bone marrow plasma cell number. In five patients, histologically or cytologically verified soft tissue myeloma lesions were correctly diagnosed by MIBI scan, while all plain radiographs showed none of them. MIBI has proven to be an effective tool in diagnosing biologically active myeloma.