Nodular lymphocyte-predominant Hodgkin’s lymphoma (NLPHL) shows constitutive NF-κB activity in the malignant lymphocyte-predominant (LP) cells. Constitutive NF-κB activity also plays a central pathogenetic role in classical Hodgkin’s lymphoma (cHL), where inactivating mutations in the NFKBIA and TNFAIP3 genes, coding for the negative NF-κB regulators IκBα and A20, respectively, contribute to NF-κB activation. To determine whether mutations in NFKBIA and TNFAIP3 are also involved in the pathogenesis of NLPHL these genes were sequenced from microdissected LP cells of 10 primary NLPHL. We also studied DEV, the only cell line proposedly derived from LP cells, after we had confirmed its derivation from NLPHL by gene expression analysis. A heterozygous somatic missense mutation in the NFKBIA gene was found in one NLPHL, and a heterozygous, possibly subclonal, two base pair insertion in TNFAIP3 in another case. The low mutation frequency and the absence of biallelic destructive mutations propose a minor contribution of NFKBIA and TNFAIP3 mutations to the NF-κB activity of NLPHL, suggesting different mechanisms of NF-κB activation in NLPHL and cHL.