An investigation was undertaken to evaluate the comparative efficacy of single dose treatment with santonin and piperazine against naturally acquiredNeoascaris vitulorumin sixty‐two buffalo calves of 20–60 days of age. Santonin was administered orally in doses of 5 mg, 10 mg and 15 mg/kg body weight to thirteen, eighteen, and sixteen buffalo calves, respectively. As a control, piperazine (88 mg/kg) was given by drench to a group of fifteen infected buffalo calves. Pretreatment and post treatment faecal eggs per gram (EPG) counts were determined by the Stoll's technique. The percentage reductions in EPG counts on the third and seventh days after administration of the two drugs were calculated. The percentage reduction in EPG counts in the piperazine treated group on the third day was 82 ± 15, 90.2 ± 3 and 91.3 ± 2.3% while on the seventh day these values were 88 ± 16, 97 ± 3, and 98 ± 2% in high, moderate and heavy infection calves, respectively. Treatment with santonin at 5, 10 and 15 mg/kg body weight also reduced the EPG counts. The percentage reduction in EPG counts in the calves treated with 15 mg/kg of santonin on the third day was 92.3 ± 18, 95.8 ± 7 and 93.5 ± 4% while on the seventh day these values were 100 ± 0, 100 ± 0 and 99.7 ± 2% in high, moderate and heavily infected calves, respectively. Both piperazine and santonin were associated with some side effects like diarrhoea, restlessness, etc. but their percentage incidence was not significantly different from each other. These findings suggest that santonin in a 15 mg/kg dose has an efficacy similar to piperazine given at the 88 mg/kg dose level for the treatment of ascariasis in