Technical Abstract: Here we describe the characterization a virulent genotype VII Newcastle disease virus (NDV) from Venezuela and evaluate the efficacy of heterologous genotype commercial vaccination under field and controlled rearing conditions. Biological pathotyping and molecular analysis were applied. Results showed mean dead time of 50 hours and an intracerebral pathogenicity index of 1.86. Phylogenetic analysis demonstrated that the virus belonged to genotype VII in the class II (a genotype often found in Asia and Africa) representing the first report of the presence of this genotype in the American continent. A vaccine-challenge trial was implemented and included dual (live/killed) 1-day-old genotype I and II NDV priming of commercial broilers plus two live NDV and Infectious bursal disease (IBDV) field vaccinations at seven and 17 days, followed by a very stringent genotype VII NDV challenge at day 28. Serology for NDV and IBDV, lymphoid organs integrity and protection against challenge were assessed. In the field group, significantly lower NDV (1.356 vs 2.384) and higher IBD (7295 vs 1489) ELISA antibody titres were observed. Lower bursal size and bursa-body weight ratio (P<0.05) and higher bursa lesions score were detected in the commercial set. Only 57.1% field vaccinates survived the lethal challenge, differing (P<0.05) from 90.5% survival in the experimental farm. Overall, results suggest that field associated factors such as immunosuppression or quality of vaccination procedures may compromise the protection provided by the heterologous genotype vaccine program against the novel genotype VII isolate herein reported and may be responsible for the ND outbreaks in Venezuela.