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Acute puerperal metritis (APM) is an acute systemic illness with fever ≥39.5°C and signs of toxemia due to an infection of the uterus occurring within 21 d after parturition. Because of the infectious nature of APM, antibiotics are considered beneficial for its treatment. Each use of an antimicrobial drug, however, is associated with selective pressure for the emergence of resistant bacteria. Hence, there is a significant need to encourage prudent use of antibiotics and alternative therapies to antibiotics. Therefore, the objective of this study was to systematically review the current literature on treatment of APM. A comprehensive and systematic literature search was conducted utilizing the PubMed and CAB Abstracts databases to identify literature focusing on the antibiotic therapy of puerperal metritis in the cow. After application of specific exclusion criteria, 21 publications comprising 23 trials remained for final evaluation. Data extraction revealed that the majority of the studies (n = 19) were attributable to the highest evidence level. Of 21 studies controlled, 11 had an untreated group and 3 a positive control group. The majority of the studies (n = 17) applied ceftiofur for the treatment of APM. Concerning the efficacy of ceftiofur, 7 studies observed clinical improvement, whereas none found improved reproductive performance. Fewer than half of the studies (n = 10) performed a bacteriological examination and only 4 implemented an antibiotic susceptibility test. Also, 3 studies (13.0%) described a self-cure rate per se. Little attention was given to the issue of bacterial resistance (n = 3), the need for reducing the application of antibiotics (n = 2), or guidelines for prudent use of antibiotics (n = 1). Our findings demonstrate that implementation of bacteriological examinations, sensitivity testing, and determination of minimum inhibitory concentrations, as well as reporting and discussion of critical issues (e.g., self-cure rates, resistance, prudent drug use), were suboptimal. On the other hand, the quality of studies on the treatment of APM was good, as indicated by evidence level 1. Nevertheless, more high-quality research considering self-cure rates is necessary to address critical issues related to APM and crucial to the dairy industry, such as resistance, prudent use of antibiotics, animal welfare, and cost-benefit ratios.