Currently, there is no definite consensus regarding the best index to assess disease activity with fluorodeoxyglucose-PET imaging. Maximum standardized uptake value (SUVmax) is most frequently used in day-to-day practice for this purpose. This approach very often reflects the metabolic activity of only a small sample of the total ongoing process in the entire body. Here we introduce a new concept called metabolic burden (MB) to measure disease activity in cancer patients. MB was calculated by measuring the volume (VCT) around a lesion that appeared on computed tomography (CT), the mean SUV that appeared on PET of the CT volume (SUVmean CT), and the recovery coefficient (RC) using the following formula: (Equation is included in full-text article.) If CT was unavailable, a region of interest (ROI) around the lesion was defined by a 40% SUVmax threshold and the volume and SUVmean were determined for that ROI. The whole-body metabolic burden (WBMB) was calculated as the sum of the individual MBs of all the lesions identified. We retrospectively reviewed 19 patients with non-Hodgkin's lymphoma who were treated with commercially available anti-CD20 radioimmunotherapy agents or conventional chemotherapy. All had a pretreatment and posttreatment fluorodeoxyglucose-PET and CT scan within 1-3 months of receiving systemic therapy. Either abnormal areas appearing on PET alone or corresponding lesions on CT were used to calculate the tumor volume (TV). Nodes of less than 2 cm occurring in clusters were grouped together into a single ROI. Thirty-eight regional collections in 14 patients were found in combined pretreatment and posttreatment studies and were assessed. The TVs varied in pretreatment size from 5.8 to 857 cm and posttreatment from 0 to 81 cm. Pretreatment WBMB varied from 27 to 10 218 cm and posttreatment from 0 to 279 cm. We then compared the standard indices of SUVmean and SUVmax with those of WBMB to determine which of the indices would have the best sensitivity as a predictor of therapeutic response. Five of the 19 patients had a complete response. In 14 patients with partial response, the average change in WBMB was 80%, the TV decreased by 76%, the SUVmax decreased by 42%, and the SUVmean decreased by 38.5%. The results of this analysis demonstrate that measurement of WBMB may prove to be superior to the existing methods in assessing and managing patients with non-Hodgkin's lymphoma. This index may be the best way to monitor the changes in WBMB as a patient is undergoing treatment.