Differences in the early responses of two potato cultivars, Igor and Nadine, to two isolates of Potato virus Y (PVY), the aggressive PVYNTN and the mild PVYN, were monitored. Microarray and quantitative real-time PCR analyses were carried out to identify differentially expressed genes after inoculation with each virus isolate. Additionally, symptom severity and development was observed and the amount of virus isolate accumulated in systemically infected leaves was evaluated, where a significantly higher amount of PVYNTN was detected. Microarray analysis revealed 572, 1288 and 1706 differentially expressed genes at 0·5, 12 and 48 h post-inoculation, respectively in cv. Igor, with a similar pattern observed in cv. Nadine. Microarray and quantitative real-time PCR results implied an earlier accumulation of sugars and lower photosynthesis in leaves inoculated with the aggressive isolate than in leaves inoculated with the mild isolate. The PVYNTN isolate did not activate early differential expression of the Fe-superoxide dismutase and pectin methylesterase inhibitor (PMEI) genes, indicating a delay in plant response relative to that following PVYN inoculation. Differences in the expression of the β-glucanase-I gene were also observed in early plant responses to inoculation with each virus isolate.