The efficacies of 20 mg/kg body weight (BW) of toltrazuril (Toltra) 2 days post-infection (dpi), 2 mg/kg BW of diclazuril 2 and 3 dpi and 200 mg/kg BW of sulphadimidine 2, 3 and 4 dpi were compared in a model for piglet isosporosis. Weight gain (first 4 weeks of life) and diarrhoea and oocyst excretion from 4 to 11 dpi were evaluated (10-12 piglets/group). Additionally, animals were killed and examined for pathohistological changes of the small intestines 5, 7, 11 and 14 dpi (n = 3 per group and time point) and lengths of the intestinal villi. Diarrhoea (semi-liquid or liquid faeces) was seen from 5 dpi in all groups except Toltra, and the differences in prevalence and intensity of diarrhoea were statistically significant (p < 0.05) between Toltra and the other groups, which were similar (trial 1). Oocyst excretion was greatly reduced in the Toltra group, which was also statistically significant for the mean and median excretion rates and the percentage of excreting piglets between Toltra and the other groups (p < 0.05). Weight gain was highest in Toltra (p < 0.05). Histopathology revealed mostly villous necrosis and atrophy in the small intestines except the duodenum, which peaked at 7 dpi, in all groups except Toltra. Between 5 and 11 dpi, the Toltra group had significantly longer villi than the other groups. Reduced weight gain and diarrhoea caused by Isospora suis was controlled by a single application of Toltra in the pre-patent period, while neither diclazuril nor sulphadimidine improved the clinical picture of isosporosis.