The protection induced by immunostimulating complexes (ISCOMs) against bovine respiratory syncytial virus (BRSV) was evaluated and compared to that of a commercial inactivated vaccine (CV) in calves with BRSV-specific maternal antibodies. Following experimental challenge, controls (n = 4) and animals immunized with CV (n = 5) developed moderate to severe respiratory disease, whereas calves immunized with ISCOMs (n = 5) remained clinically healthy. BRSV was re-isolated from the nasopharynx of all controls and from all calves immunized with CV, but from none of the calves immunized with ISCOMs. BRSV-RNA was detected by real-time PCR from a single animal in this group. Significantly higher BRSV-specific nasal IgG, serum IgG ₁ and IgG ₂ titers were detected before and after challenge in animals immunized with ISCOMs versus CV. In conclusion, the ISCOMs overcame the suppressive effect of maternal antibodies in calves and induced strong clinical and virological protection against a BRSV challenge.