Acute puerperal metritis (APM) in dairy cows is often treated with antibiotics. An increasing antibiotic resistance is well documented and associated with decreasing clinical efficacy, animal welfare and economic consequences. Hence, there is a significant need to encourage prudent use of antibiotics and alternative therapies to antibiotics. The objective of this study was to compare the efficacies of ketoprofen and ceftiofur for the treatment of APM. Between June 2013 and February 2015, a total of 610 dairy cows from 6 farms in Germany were enrolled. Inclusion criteria was a rectal temperature (RT) ≥ 39.5°C and a reddish-brown fetid vaginal discharge within the first 10 DIM. Cows meeting the inclusion criteria were randomly allocated to treatment with ketoprofen (3 mg/kg of BW, n = 300) or treatment with ceftiofur (1 mg/kg of BW, n = 310), both on 3 consecutive days. Rectal temperature was recorded daily for a period of 7 d after enrollment. Cows that showed RT ≥39.5°C on d 4 to 7 after inclusion received an extended treatment with ceftiofur for 3 (ketoprofen group) or 2 (ceftiofur group) more days. Between 21 and 34 DIM, cows were examined with the Metricheck device and vaginal discharge was categorized on a 5-point scale according to the presence of pus. A total of 51 cows (34 from ketoprofen group, 17 from ceftiofur group) were excluded from analysis due to concurrent disease (n = 15), additional medication of APM (n = 11), and due to missing protocol compliance (n = 25). Cows of the ketoprofen group (54%) received an extended treatment more often than cows of the ceftiofur group (30%; P < 0.01). Occurrence of purulent vaginal discharge was similar for both treatment groups (ketoprofen: 57.8%, ceftiofur: 55.3%, P = 0.62). More than half of the cows initially treated with ketoprofen needed ceftiofur treatment. However, there is potential of reducing antibiotic use by utilizing ketoprofen for the treatment of APM as up 46% of cows treated with ketoprofen did not need extended treatment. Animal welfare and economic aspect need to be considered.