Background: Dosimetry has been used to help identify when empiric dosages of 131-I treatment for suspected metastatic well-differentiated thyroid carcinoma (WDTC) may be increased or should be decreased, but dosimetry is complex, and easier approaches would be useful. The three objectives of this study were to assess the utility of the percent whole-body retention of 131-I at 48 hours (%WBR48hr) in identifying patients with WDTC in whom the therapeutic empiric prescribed activity of 131-I might be increased/decreased, to evaluate the thresholds proposed by Sisson et al. in 2003 for increasing or decreasing activity, and to determine the relationship between %WBR48hr and maximum tolerated activity (MTA). Method: A retrospective review was conducted of patients who had WDTC, total thyroidectomy, suspected metastatic disease, thyroid hormone withdrawal, and 131-I dosimetry. The %WBR48hr was determined based on the Benua-Leeper dosimetry protocol, and the four thresholds and recommendations of Sisson et al., 2003 for the use of %WBR48hr were evaluated relative to an empiric activity (EA) of 7.4 GBq of 131-I. A biexponential equation was determined from the %WBR48hr data. Results: Of 142 patients, 47 patients had a %WBR48hr of <9%, and all could have received more than the EA of 7.4 GBq with an average of 21.0 GBq (incremental range of 6.8–23.2 GBq). Ten patients had a %WBR48hr ≤ 5%, and all could have had their EA of 7.4 GBq safely increased by at least 250%. Conversely, if the %WBR48hr was >24.8%, then 7 of 14 of these patients would have exceeded the MTA by 0.37–3.18 GBq with an EA of 7.4 GBq. Finally, for patients with a %WBR48hr > 40%, five of six patients would have exceeded the MTA by 0.85–3.18 GBq. A biexponential regression equation is presented. Conclusion: We conclude that, with respect to the treatment of metastatic epithelial cell thyroid cancer, the %WBR48hr of 131-I helps identify those patients in whom the empiric therapeutic prescribed activity of 131-I may be increased or should be decreased so as not to exceed the MTA and that Sisson et al.'s thresholds published in 2003 are applicable. We favor a biexponential regression model using the %WBR48hr and a lower limit threshold as a potentially useful method for determining how much an empiric therapeutic prescribed activity of 131-I can be increased or decreased.