Potato virus Y (PVY) is one of the most destructive viruses infecting potato in Egypt and worldwide. Recent research has shown that a necrotic PVY-NTN strain is infecting potato in Upper Egypt. Chemical control is not effective to control this viral pathogen. An alternative to control PVY infecting potato is using a mild PVY strain to elicit systemic cross protection in potato plants against infection with a severe necrotic strain of PVY. Results of this study showed that a PVY necrotic strain produced a significant lesser number of local lesions on diagnostic plants (Robinia pseudoacacia L.) when these plants were treated first with a mild PVY strain. Data obtained from greenhouse and field experiments indicated that treatment of potato plants (variety Burna) with a mild PVY strain significantly protected potato from infection with a severe necrotic PVY strain, and resulted in a significant increase in tuber yield compared with infected plants without prior treatment with a mild PVY strain. The highest increase in potato tuber yield was obtained when potato plants were inoculated with a mild PVY strain 3 days before challenging with the severe necrotic PVY strain. This study proved that using a mild strain of PVY can significantly protect potato plants from infection with a severe strain of this virus under both greenhouse and field conditions and can present a potential method to reduce losses due to infection of this virus in Assiut governorate and Upper Egypt.