The objective of the study was to compare the systemic antibiotic treatment of clinical endometritis in dairy cows with ceftiofur with a treatment protocol consisting of two doses of prostaglandin F(2alpha) analogue cloprostenol in a 14-d interval. On 2 commercial dairy farms, housing a total of 1900 Holstein cows, all cows that calved between June 2008 and January 2009 were examined 21-27d in milk (DIM) by vaginoscopy. Cows with clinical signs of endometritis, i.e. vaginal discharge containing flecks of pus, mucopurulent material or purulent mucus, were randomly allocated to one of two treatment groups. Cows in group CEF (n=141) received 1 mg/kg BW of ceftiofur (i.m.) on 3 consecutive days. Cows in group CLP (n=140) received 0.5 mg of cloprostenol (i.m.) at the day of enrolment and 14d later. All cows were re-examined by vaginoscopy 42-48 DIM. Proportion of cows cured, i.e. cows with clear, translucent or no mucus, 42-48 DIM (74.2 and 80.2% in groups CEF and CLP, respectively) was not affected by treatment group (P=0.09). The voluntary waiting period was set at 40 DIM. Artificial insemination (AI) submission rate, days to first service, first service conception rate, days open and proportion of cows pregnant did not differ between the groups. In conclusion, the systemic treatment with 1.0 mg/kg BW of ceftiofur on 3 consecutive days in cows with signs of clinical endometritis 21-27 DIM was equivalent to an intervention protocol consisting of two doses of cloprostenol in a 14-d interval.