Vaccine failures after Newcastle disease vaccination with the current commercial vaccines have been reported and are associated with many factors, including genotypic and antigenic differences between vaccine and outbreak strains, although all APMV-1 members belong to one serotype. We assessed the immunoprotection ability of four thermostable, low-virulent Newcastle disease-virus isolates from Ugandan waterfowl against challenge with a virulent strain (MDT = 36.8 h, ICPI = 1.78) isolated from morbid chicken. Six-week-old commercial Leghorn layers, challenged at 21 days post immunization were used. Four isolates designated: NDV-133/UG/MU/2011, NDV-177/UG/MU/2011, NDV-178/UG/MU/2011 and NDV-173/UG/MU/2011 induced mean haemagglutinin inhibition antibody titres of log 9.3, 8.2, 6.3 and 2.0, respectively, at 21 days post immunization. The antibody titres correlated with the protection rates (R² = 0.86, p < 0.007) of 60%, 50%, 20% and 0% of birds, respectively, against challenge at 14 days post challenge. Further evaluation of these and more low-virulent isolates might provide an alternative to the current commercial vaccine failures.