Spontaneous regression of non-Hodgkin lymphoma (NHL) has been reported in low-grade tumors but is an extremely rare event in intermediate- and high-grade disease. Documentation of spontaneous regression by serial fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging has not been reported in the literature. We present 3 cases of spontaneous regression, 1 each of follicular lymphoma (FL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), which showed spontaneous regression on serial FDG-PET imaging. All patients underwent serial whole-body FDG-PET scans 60 minutes after intravenous injection of 9-11 mCi of this radiotracer. None of them had any chemotherapy, radiotherapy, or surgery after the baseline PET scan. Spontaneous regression of disease in all 3 cases was correlated with conventional imaging and clinical course. All 3 patients had positive FDG-PET results on their baseline scan. There was complete disappearance of FDG uptake on a follow-up PET scan for the patient with follicular lymphoma. These results suggest complete regression. The patients with MCL and DLBCL both showed a significant reduction in FDG uptake on serial whole-body PET scans, suggesting partial regression in both cases. Although spontaneous regression of lymphoma is uncommon, this phenomenon can be successfully demonstrated by FDG-PET imaging. Therefore, serial PET imaging may play an important role in detecting this unusual event and may further enhance our understanding of the biologic behavior of this malignancy.