A Large number of short interfering RNAs (siRNAs) are generated from plant viruses during infection, but their function, character and biogenesis are unclear. Here, we analyzed the viral small RNA profile in tomato plants upon Cucumber mosaic virus (CMV) Fny strain infection, using highthroughput deep sequencing techniques. A set of 129666 CMV-Fny-specific small RNAs, most of the 21-(54.6%) and 22-nucleotide (28.2%) in size were obtained. Both strands of CMV-Fny were substrates for production of viral-specific siRNAs, and the virus genome harbored multiple, highly reproducible small RNA-generating hot spots that corresponded to regions with no apparent local hairpin-forming capacity. In addition, using the novel high throughput degradom sequencing approach and informatics analysis, we found a large set of host genes could be potentially targeted by CMV-Fny-derived siRNAs for posttranscriptional silencing. Six of such host targets were further validated by qRT-PCR. Gene ontology analysis with biological process, cellular component and molecular function terms revealed that these target genes mainly related to stress response, cell redox homeostasis, protein folding/stabilization/transport, chloroplast-and photosynthesis-related processes, metal ion binding, ATP binding, jasmonic acid mediated signaling pathway, and gene silencing by RNA. These results indicate that the production of viral derived siRNAs might be involved in virus-host interactions, and could contribute to explain how pathogens cause symptoms in their hosts.