Background: There is limited published information on the outcome for cats where total thyroxine concentration (TT4) remains elevated after treatment with radioactive iodine (RAI).Objective: To determine the frequency of, and predictors for, subsequent treatment failure in cats for which TT4 remains elevated at hospital discharge, and to report clinical outcomes for cats requiring repeat treatment.Animals: One hundred twenty-one cats with TT4 ≥40 nmol/L after treatment with RAI (out of an original, treated study sample of 959 cats).Methods: Retrospective study. Data regarding signalment, weight, TT4 concentration (before RAI treatment, at discharge, and percentage change), day of sampling, and I-131 dose were acquired. Logistic regression was performed to evaluate predictors of treatment failure.Results: In the 87 cats for which classification was possible, 35 (40%) became euthyroid without further treatment. All TT4 variables and weight normalized RAI dose were independently predictive of subsequent treatment failure. In multivariate analysis, TT4 concentration at discharge (P < .001) and weight normalized RAI dose (P = .04) remained in the final model. All 28 cats with TT4 concentration ≥150 nmol/L at discharge ultimately failed treatment, compared with 13/40 (32.5%) and 11/19 (57.9%) cats with TT4 concentrations of 40-100 nmol/L and 100-150 nmol/L, respectively. Of the 52 cats that failed treatment, 14 were subsequently managed medically, 12 underwent thyroidectomy (4 with carcinoma), 14 had repeat RAI treatment which was successful in 12/14 (86%) cats, and 13 had no further treatment.