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Background/Objectives: In swine production, the post-weaning period has been identified as one of the most challenging and stressful periods in the life of a piglet due to changes in its environment and feeding regimen. During this period, piglets might undergo infectious challenges with enterotoxigenic Escherichia coli (ETEC) resulting in post-weaning diarrhea (PWD), and meningitis due to Streptococcus suis. Therefore, metaphylactic and curative antimicrobial therapy is frequently applied, which leads to an increased treatment incidence per 100 days at risk (TI₁₀₀). Methods: Here, we report the results of an antimicrobial coaching trajectory in a 1000-sow farm with high antimicrobial use during the post-weaning period. For a period of 21 weeks, we evaluated the effect of an oral live avirulent E. coli F4F18 vaccine (Coliprotec^® F4F18; Elanco AH) for the active immunization of piglets against PWD caused by F4- and F18-ETEC on the reduction in antimicrobial use during the post-weaning period. A 1000-sow farm with PIC sows operating in a 1-week BMS was rated as an ‘attention farm’ at the level of the post-weaning period according to the Antimicrobial Consumption and Resistance in Animals (AMCRA) benchmark reporting tool. To analyze the specific approach towards antimicrobial use and the related post-weaning pathology, a farm visit including a biosecurity check was carried out together with all associated stakeholders. Subsequently, an antimicrobial coaching trajectory was utilized to follow-up on the improvement of the reduction in antimicrobial use after implementation of the various pieces of advice. Results: For analytical purposes, we compared the results obtained in period 1 (P1; vaccination week 1–6) to period 2 (P2; vaccination week 7–21), since practical field experience has demonstrated that a ‘stabilization period’ of about 6 weeks is necessary to obtain the maximal effect of vaccination. There was a significant reduction in mortality (5.7% to 2.0%) and improvement in the average daily weight gain (366 g/d to 392 g/d) following vaccination, with a simultaneous reduction in the number of days in nursery (45 days to 38 days). Meanwhile, the weight at the end of nursery remained at a similar level. There was a clinically relevant though non-significant decrease in the TI₁₀₀ (32.8 days to 20.6 days). Overall, the implementation of all measures resulted in a positive ROI of 2.72 per piglet. Conclusions: The implementation of several biosecurity measures in combination with the use of an oral live avirulent E. coli F4F18 vaccine (Coliprotec F4F18) could improve performance parameters and reduce mortality, while reducing the number of days in nursery and the TI₁₀₀. Overall, a positive return on investment of 2.72 could be obtained per piglet produced under these improved conditions. Full article