Viroids are unique RNA entities that infect higher plants. Their non-coding genome provides a specific structural signature that withdraws host factors to ensure its replication, movement and pathogenesis. PSTVd is a nuclear localized viroid that uses the cellular RNA pol II to multiply its genome by an asymmetric mode of rolling circle mechanism. PSTVd infects different types of crops, causing disturbances in their growth and development, which leads to reduced yields and economic losses. We study the PSTVd response of two Bulgarian pepper cultivars (Kurtovska kapia and Djulunska shipka) at 43 day post infection (dpi) by applying a next-generation RNA sequencing. At the phenotype level, the two pepper cultivars showed a difference in the severity and timing of symptoms. At molecular level, the comparison of transcriptome data uncovered multiple altered genes, some of which showed opposite expression patterns in the two cultivars. Some of them were associated with hormonal signalling and ROS scavenging action, and selected for further analysis by RT-qPCR. The obtained data might highlight the pepper cultivar-specific defense mechanisms against PSTVd.