Abstract Background Radioiodine (131I) is the treatment of choice for cats with hyperthyroidism. After 131I, however, euthyroidism is not always achieved, with 5% to 10% of cats remaining persistently hyperthyroid and 20% to 50% developing iatrogenic hypothyroidism. Objectives To identify pretreatment factors that may help predict persistent hyperthyroidism and iatrogenic hypothyroidism after treatment of cats using a novel 131I dosing algorithm. Animals One thousand and four hundred hyperthyroid cats treated with 131I. Methods Prospective, before‐and‐after study. Pretreatment predictors (clinical, laboratory, scintigraphic, 131I dose, 131I uptake measurements) of treatment failure or iatrogenic hypothyroidism were identified by multivariable logistic regression analysis. Results Cats that developed iatrogenic hypothyroidism were more likely to be older (odds ratio [OR] = 1.10; 95% confidence interval [CI], 1.04‐1.17; P = .001), female (OR = 2.04; 95% CI, 1.54‐2.70; P