Despite recent advances in our understanding of classical HL (cHL) the pathogenesis of this disease is still largely unknown. For instance, only a few genetic aberrations in the tumor cells of cHL, the Hodgkin and Reed/Sternberg (HRS) cells, have been identified. In general, the analysis of HRS cells is hampered by the rarity of the HRS cells which usually comprises only about 1% of the tumor tissue. To better understand the pathogenesis of cHL and to identify new genes critically involved in this process, we developed a method to perform whole exome sequencing of microdissected HRS cells. So far 11 primary cHL cases were successfully sequenced. The successful validation of 16 of 21 selected mutations in HRS cells of three cHL cases by direct PCR with microdissected cells and Sanger sequencing showed the reliability of the analysis. In a preliminary analysis of the data, NFKBIE mutations were identified in three cases. Thus, NFKBIE mutations are a recurrent event in cHL.