The malignant Hodgkin- and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) highly and consistently express CD30 on their cell surface, which is used for its diagnosis and since recently targeted therapy with drug-conjugated CD30-specific antibodies. However, the role of CD30 in the pathogenesis of cHL is not well understood and controversially discussed. We established a CRISPR/Cas9 system in CD30-positive lymphoma cell lines and confirmed efficient knockout of CD30. Characterization of CD30-depleted cHL cell lines identified a growth disadvantage under competitive growth conditions and CD30-knockout cultures showed increased cell death, which was at least partly mediated by apoptosis. Influences of CD30 on the activity of a main signaling pathway driving cHL lymphomagenesis, i.e., NF-κB signaling, were detected. Furthermore, contribution of CD30 signaling to the high MYC activation signature of cHL cell lines was identified. These results point to an important role of CD30 expression by HRS cells for the pathobiology of cHL.