Maternally derived antibodies (MDA) are known to provide early protection from disease but also to interfere with vaccination efficacy of young chicks. This interference phenomenon is well described in the literature for viral diseases such as infectious bursal disease, Newcastle disease (ND), and avian influenza (AI). The goal of this work was to investigate the impact of H5 MDA and/or ND virus (NDV) MDA on the vaccine efficacy of a recombinant NDV-H5–vectored vaccine (rNDV-H5) against two antigenically divergent highly pathogenic AI (HPAI) H5N1 challenges. In chickens with both H5 and NDV MDA, a strong interference was observed with reduced clinical protection when compared to vaccinated specific-pathogen-free (SPF) chickens. In contrast, in chickens from commercial suppliers with NDV MDA only, a beneficial impact on the vaccine efficacy was observed with full protection and reduced viral excretion in comparison with rNDV-H5–vaccinated SPF chickens. To distinguish between the respective effects of the H5 and NDV MDA, an SPF model where passive immunity had been artificially induced by inoculations of H5 and NDV hyperimmunized polysera, respectively, was used. In the presence of H5 artificial MDA, a strong interference reflected by a reduction in vaccine protection was demonstrated whereas no interference and even an enhancing protective effect was confirmed in presence of NDV MDA. The present work suggests that H5 and NDV MDA interact differently with the rNDV-H5 vaccine with different consequences on its efficacy, the mechanisms of which require further investigations.