The present randomised, controlled, multi-centre study investigated the non-inferiority of a transdermal application of thiamazole nanocarrier-ointment versus the oral administration of thiamazole tablets for the treatment of feline hyperthyroidism. The study concluded for the period from December 2016 to April 2018, during which cats with a serum T4 concentration of > 4.5 µg/dl (58 nmol/l) were included in the study and randomly assigned to the dermal or oral treatment group. Cats in the dermal group received a dose of 3.6 mg (T4 value > 4.5–10 µg/dl resp. > 58–129 nmol/l) or 7.2 mg (T4 value > 10 µg/dl resp. > 129 nmol/l) daily, depending on the initial T4 value. Those in the oral group received 5.0 mg daily, regardless of the T4 value. The primary endpoint was the proportion of euthyroid cats (T4 value 0.8–4.0 µg/dl resp. 10–51 nmol/l) in the per-protocol population after 16 weeks of treatment regarding the non-inferiority in the dermal versus the oral treatment group. A difference in success rates between the two groups of 10 % was set in advance as the non-inferiority threshold. The dermal group was deemed not to be inferior if the lower 95 % confidence interval was greater than -10 %. A limit of 0 % was defined for further analyses for superiority. A total of 88 cats (dermal group 53, oral group 35) were included in the per-protocol analysis. At day 21, 42, 63 and 120, 72 %, 77 %, 83 % and 83 % of the dermal group and 46 %, 63 %, 65 % and 54 % of the oral group were euthyroid, respectively. Non-inferiority was demonstrated at all control points and superiority of the dermal group over the oral group was demonstrated at day 21 and 120 (confidence intervals at weeks 3, 6, 9 and 16: 6–47 %; -5–34 %; -1–38 %; 9–48 %). The study indicates that a transdermal formulation of thiamazole based on CMS nanocarriers was not inferior in efficacy to oral treatment at any point in the study and can be evaluted as a safe treatment option.