Retained placenta is a worldwide recognized clinical condition in puerperal cows, which can significantly affect their health and fertility. Available treatment modalities are often of questionable efficacy or associated with time constraints, practicality or monetary considerations for their wide application in a routine dairy practice. The objective of this study was to compare and assess the efficacy of different treatment options, including a novel ozone treatment, for the retained placenta. Two hundred cows diagnosed with retained placenta were divided into five treatment groups, each receiving a different treatment option. Group A (n = 40) was given a combination treatment of intrauterine ozone and parenteral cephalexin; group B (n = 40) was given intrauterine ozone; group C (n = 40) was given a combination of parenteral cephalexin and intrauterine antibiotic tablets; group D (n = 40) was given only parenteral cephalexin and group E (n = 40) was given parenteral prostaglandins in 11-day intervals. The control group (group Z, n = 200) included cows that gave birth without assistance and were not diagnosed with a retained placenta. The ozone treatment (groups A and B) was found to be the most effective modality resulting in the shortest period of days open, the smallest number of artificial inseminations until pregnancy, the smallest number of animals diagnosed with fever within 10 days post-calving, the highest percentage of animals pregnant within 200 days after calving and the smallest number of animals culled because of infertility, when compared to the other treatment groups. The intrauterine ozone flush therefore has a potential as an efficacious and cost-effective treatment option for retained placenta, with an overall positive effect on puerperal health and fertility in cows.