Potato virus Y (PVY) is one of the most economically important pathogens of potato. PVY exhibits different phenotypes in dissimilar potato cultivars. Previously, we observed that two recombinant isolates, PVYN-Wi-HLJ-BDH-2 (hereinafter referred to as BDH) and Potato virus Y (PVY) is one of the most economically important pathogens of potato. PVY exhibits different phenotypes in dissimilar potato cultivars. Previously, we observed that two recombinant isolates, PVYN-Wi-HLJ-BDH-2 (hereinafter referred to as BDH) and PVYNTN-NW-INM-W-369-12 (hereinafter referred to as 369) exhibited different virulence levels in potato cv. Kexin 13 despite high genome sequence identity. Indeed, 369 induced severe necrosis and plant death in severe cases in Kexin 13 and severe mosaic in cv. Yanshu 8, whereas BDH caused mainly mosaic symptoms on the plants of both cultivars. We hypothesized that pre-infection of plants with BDH could cross-protect them from 369 infection, and vice versa. Challenge inoculation, either by mechanical wounding or through grafting, with 369 on plants that were pre-infected with BDH did not augment the symptom expression in both cultivars. Reverse transcription-quantitative PCR (RT-qPCR) analysis showed that, after challenge inoculation with 369, the titer of the isolate on BDH-pre-infected plants remained at a relatively low level (~ 3 x104 copy/µL) during the tested time course (0 h -30 days). In contrast, in plants that were pre-inoculated with buffer (mock) and challenge inoculated with 369, the titer of 369 increased continuously until reaching its highest level of ~2 x107 (Yanshu 8) - ~ 4 x108 (Kexin 13) during the time course. Surprisingly, in plants that were pre-infected with 369 and challenge inoculated with BDH, the accumulation of BDH reached nearly the same level (~mid to high x108) as that in plants that were pre-inoculated with buffer and challenge inoculated with BDH. Taken together, these results suggest that PVYN-Wi mediated cross-protection against PVYNTN-NW by superior competition and better fitness.