Introduction: It is not clear whether high-activity radioactive iodine (131I) treatment will affect renal function. This study aimed to investigate the effects of high-activity 131I treatment on the clinical metrics of renal function in patients with differentiated thyroid carcinoma (DTC). Material and methods: 262 DTC patients with abnormal baseline renal function (group A) and 262 DTC patients with normal baseline renal function (group B) who received 131I therapy were analysed. Each group was further divided into three subgroups based on the cumulative activity of 131I: subgroup 1 if the cumulative activity was less than 11.1 GBq; subgroup 2 if the cumulative activity was between 11.1 GBq and 18.5 GBq; and subgroup 3 if the cumulative activity was more than 18.5 GBq. The clinical metrics of renal function including serum creatinine (SCr), blood urea nitrogen (BUN) and estimated glomerular filtration rate (eGFR) were measured and compared before initial 131I treatment and 5 years later. Result: There was no significant difference of the demographics between the two groups. In group A, SCr and BUN levels were elevated in 186 and 113 patients, respectively, and eGFR was decreased in 108 patients before the initial 131I therapy. SCr and BUN levels were found to be increased in all subgroups 5 years after the initial 131I therapy; furthermore, eGFR was found to be decreased in all subgroups after 131I therapy, and the difference was statistically significant (p < 0.05). A gender bias was not observed in the changing trends of SCr and BUN levels and eGFR. In group B, no significant difference in the mean levels of SCr, BUN, and eGFR was observed in the 3 subgroups (p > 0.05), regardless of gender, before the initial 131I therapy and 5 years later. A total of 5, 2, and 2 patients presented with abnormal renal function after 131I treatment in subgroups 1, 2, and 3, respectively. No statistically significant difference was observed in the incidence of renal dysfunction among the 3 subgroups (p = 0.423). Conclusion: Our findings suggest that the nephrotoxicity of high-activity 131I therapy, regardless of gender, is very low in patients with DTC with normal renal function; however, high-activity 131I therapy may exacerbate the loss of renal function in those with renal dysfunction.