Bovine tuberculosis (bTB) is a zoonotic disease caused mainly by Mycobacterium bovis, of which control is based on culling infected animals and, without official compensations, is associated with major economic losses for milk and meat producers. The vaccination of cattle with the M. bovis Bacillus Calmette-Guerin (BCG) strain, as a strategy for bTB control, might attenuate this situation. The objective of this trial was to assess the efficacy of the BCG Russia strain in a cohort study performed under field conditions, with the vaccination of 501 calves in seven dairy farms, including 441 non-vaccinated control animals. Peripheral blood was collected at 6, 12 and 18 months post-vaccination, and infection status was determined using a diagnostic procedure which discriminates the infected amongst vaccinated animals. On average, the BCG vaccine showed a low but significant level of protection (22.4%) at the end of the trial, although diverse levels of protection and duration of immunity were observed between trial herds, suggesting that the efficacy of the BCG vaccination could be influenced by the general health condition of calves and their exposition to non-tuberculous mycobacteria. These results support the use of BCG as a complementary tool in the control of the disease in high prevalence areas. Bovine tuberculosis (bTB) is a zoonotic disease caused mainly by Mycobacterium bovis, which is associated with major economic losses for milk and meat producers. The objective of this trial was to assess the efficacy of the BCG Russia strain in a cohort study performed under field conditions, with the vaccination of calves in seven dairy farms from a high prevalence area in central Chile. The trial was performed with 501 animals, subcutaneously vaccinated with 2-8 × 10 5 colony-forming units of BCG, whilst 441 matched control animals received a saline placebo. Peripheral blood was collected at 6, 12 and 18 months post-vaccination, and infection status was determined using the IFNγ release assay in conjunction with the DIVA (Detecting Infected amongst Vaccinated Animals) antigens ESAT-6, CFP-10 and Rv3615c. The BCG vaccine showed a low but significant level of protection of 22.4% (95% CI 4.0 to 36.4) at the end of the trial. However, diverse levels of protection and a variable duration of immunity were observed between trial herds. This diverse outcome could be influenced by the general health condition of calves and their exposition to non-tuberculous mycobacteria. These results suggest that BCG vaccination of dairy calves in a natural transmission setting confers variable protection to animals against bTB in a high prevalence area.