MicroRNAs (miRNAs) are negative regulatorsof gene expression that play an importantrole in hematopoiesis and tumorigenesis.We analyzed miRNA expressionin classic Hodgkin lymphoma (cHL) andthe influence of Epstein-Barr virus (EBV)infection on the miRNA expression profiles.The expression of 157 miRNAs inlymph nodes from 49 cHL patients and10 reactive lymph nodes (RLNs) was analyzedby real-time polymerase chain reaction(PCR). Hierarchic clustering revealed3 well-defined groups: nodular sclerosiscHL, mixed cellularity cHL, and RLNs.A distinctive signature of 25 miRNAs differentiatedcHL from RLNs, and 36 miRNAswere differentially expressed in thenodular sclerosis and mixed cellularitysubtypes. These results were validated ina set of 30 cHLs and 5 RLNs, and in 3 cHLcell lines. miR-96, miR-128a, and miR-128b were selectively down-regulated incHL with EBV. Our findings suggest thatmiRNAs play an important role in thebiology of cHL and may be useful indeveloping therapies targeting miRNAs.