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Pigs routinely undergo stressful vaccination procedures, which are often unavoidable given the unavailability of safer alternatives, challenging animal welfare. The available vaccines for Mycoplasma hyopneumoniae (Mhyo) or Porcine circovirus type 2 (PCV2) are mostly administered intramuscularly in association to prevent Porcine respiratory disease complex (PRDC). MHYOSPHERE® PCV ID is the first vaccine protecting from both agents by intradermal route. This randomized, blind-field trial aimed to compare the effects of MHYOSPHERE® PCV ID with those of three different intramuscular associations of commercially available vaccines. A total of 7072 21-day-old piglets from 12 consecutive batches in one farm were randomly vaccinated with MHYOSPHERE® PCV ID (G1) or Ingelvac CircoFLEX® + Hyogen® (G2), Porcilis® PCV + M + PAC® (G3), and Porcilis® PCV + Hyogen® (G4). Growth performance during the nursery period and adverse reactions (ARs) after vaccine administration were monitored. Average Daily Weight Gain (ADWG) during the first 7 days post-weaning in G1 was 10.92, 3.03, and 20.08 g/day higher than in G2, G3, and G4, respectively, and 0.65, 4.06, and 9.58 g/day higher than in G2, G3, and G4 during the entire nursery period, respectively. G1 ADWG was significantly higher than G4 during both periods and significantly higher than G2 during the first 7 days post-weaning. Incidence of systemic ARs in G2 and G4 was 0.03% and 0.32%, respectively; none were recorded in G1 and G3. Replacing the usual intramuscular vaccination with MHYOSPHERE® PCV ID results in higher growth performance during the first weeks after weaning with no systemic ARs.