Post-weaning diarrhea due to Escherichia coli in pigs threatens animal health and is responsible for antibiotic prescriptions. A live vaccine administered orally reduces the incidence and shedding of E. coli F4/F18. The objective of this study was to compare the course of antibiotic prescriptions and zootechnical performance before and after vaccination. Forty-five farrow-to-finish farms in which ColiprotecTM F4/F18 vaccine was administered to piglets to prevent post-weaning diarrhea were selected. Six months before and six months after the start of vaccination, data on antibiotic use and zootechnical performance were recorded. Animal Level of Exposure to Antimicrobials (ALEA) indicators, average daily gain (ADG) and mortality rate were monitored. Comparisons before and after the vaccination were made for the 45 farms and for two subsets of farms based on growth performance and mortality rate before vaccination (categories “+” and “-”, respectively higher or lower than the reference mean of the pig producers’ cooperative). After vaccination, ALEA indicators significantly decreased for the 45 farms by 68% for digestive antibiotics and by 70% for colistin (P < 0.0001). Mean ADG from weaning to slaughter was significantly higher (+22 g) for the farms in the “-” category (P < 0.0001). The mortality rate from weaning to slaughter decreased for the 45 farms (-0.84, P = 0.03) and for the farms in the “-” category (-2.00, P < 0.001). Oral E. coli F4/F18 vaccination significantly reduces the exposure of animals to antibiotics and improves zootechnical performance in pig farms.