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Advances in classification integrating phenotypic, genetic, and transcriptomic features have improved diagnosis and prognosis. However, a comprehensive and integrated molecular characterization of DLBCL cell lines is still lacking, which limits their optimal use as reliable experimental models. We employed fluorescence in situ hybridization, immunohistochemistry, and targeted DNA and RNA sequencing to identify genetic subtypes and determine the cell of origin, providing a comprehensive characterization of 29 DLBCL cell lines through the integration of phenotypic, genomic, and transcriptomic data. Principal component analysis, gene set enrichment analysis (GSEA), differential expression profiling, and regulon analysis enabled us to dissect molecular heterogeneity. We achieved high concordance in genetic subtype assignment using multiple classification algorithms (2\u2010S, LymphGen, and DLBclass). 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