•Paratuberculosis vaccination extends productive life of dairy cattle.•Paratuberculosis vaccination induces a reduced mortality non-specific effect (NSE)•This NSE fits the expected according to the trained immunity mechanism.•This inactivated vaccine has a positive effect on females.•Extended paratuberculosis vaccination could help reduce antibiotic use. Records of cattle vaccination against paratuberculosis (PTB) have been analyzed to determine whether or not non-specific effect (NSE) on overall mortality similar to that observed in BCG vaccinated humans occurs in animals. The results of a previously reported slaughterhouse study on PTB prevalence were used as a reference on the age incidence of advanced patent (clinical) epidemio-pathogenic forms. In the proper vaccine study, cows in 30 cattle farms in the Basque Country, Spain were followed-up for between 1 and 13 years. Vaccinated groups were composed by 1008 (592 right-censored) animals younger than 3 months treated as calves and by 3761 (3160 right-censored) vaccinated at any older age. Controls were 339 (157 right-censored) and 4592 (2213 right-censored) age matched animals, respectively. Individual last year presence in the annual testing was considered age at culling or death. A survival analysis was carried out according age at vaccination of vaccinated versus non-vaccinated animals. PTB age incidence in the slaughterhouse study was subtracted from the difference between vaccinated and non-vaccinated animals at the same age in order to estimate PTB-specific and non-specific effects. The maximum difference was observed at the 2–3 years interval with a 33.9% mortality reduction in the calf vaccinated group. This corresponded also with the maximum NSE that was 24.5% for a PTB incidence of 9.5%. Overall, vaccination afforded to calves a 26.5% yearly mortality protection, split between 11.1% PTB-specific and 15.4% NSE. These results support a NSE on total mortality associated with PTB vaccination that appeared to persist for up to 6–7 years. This confirms for the first time in an animal field study the innate immune system memory predicted by the recently proposed trained immunity theory. Contrasting the literature, no deleterious effects of killed vaccines on females were observed. Mortality reduction would offset vaccination costs and could improve livestock systems efficiency and potentially reduce antibiotic use. Clinical trial registered with Spanish Agency for Drugs and Sanitary products (AEMPS) as 11/012/ECV.