The combined, intradermal application of multiple vaccines against key diseases in swine offers many benefits, including reduced time and labor costs, and improved animal welfare due to fewer injections and manipulations. This study investigated the efficacy of a newly developed intradermal combination vaccine for Porcine circovirus 2 (PCV2) and Mycoplasma hyopneumoniae (M hyo) (PCV M Hyo ID vaccine) in swine. The vaccine was evaluated for its efficacy against PCV2 and M hyo infection and its concurrent mixed use with Lawsonia intracellularis (LI) and non-mixed use with Porcine reproductive and respiratory syndrome virus (PRRSV) vaccines. The findings demonstrated that the PCV M Hyo ID combination vaccine is efficacious against PCV2 and M hyo infection. Furthermore, the new PCV M Hyo ID combination vaccine can also be administered simultaneously and at the same anatomical location after mixing with LI ID vaccine, and next to PRRS ID vaccine, to efficiently protect pigs from all four major diseases in swine. The efficacy with the combination of vaccines was equivalent to that of the single vaccines.