Homologous and heterologous viral interference is a common occurrence that has been well studied in vitro. In the present study, homologous viral interference between the LaSota and NYP strains of Newcastle disease virus (NDV) was studied in vivo in chickens, the natural host for NDV. The LaSota strain is avirulent and widely used as a vaccine in poultry industry, while the NYP strain is highly virulent and causes acute disease and death in chickens within four to six days after infection. Chickens generally became resistant to NYP strain challenge 12 hours after intranasal or intratracheal inoculation with LaSota strain virus. The resistance was manifested by reduction in chicken morbidity and mortality, decrease in virus replication in the chicken respiratory tract (p less than 0.05), and inhibition of NYP strain induced gross and microscopic lesions. Interferon was first detected in the chicken respiratory tract and blood at 3 to 6 hours; it peaked at 12 to 24 hours and was maintained for 48 hours after viral inoculation, indicating that interferon induction might be one possible mechanism of the interference between the two strains. This study suggests a role for viral interference in vaccination against virulent viruses.