The sole distinguishing feature of follicular lymphoma grade 3B and diffuse large B-cell lymphoma is the growth pattern assessed by histopathology. Diffuse growth defines diffuse large B-cell lymphoma but the clinical relevance of this finding when occurring in follicular lymphoma grade 3B is uncertain. To address this issue, individual and coexisting follicular lymphoma grade 3B and diffuse large B-cell lymphoma were separated and analyzed for immunophenotype and molecular genetic features by fluorescence in situ hybridization, targeted sequencing and gene expression profiling. Clinical features of follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma were studied in homogeneously treated patients from a prospective randomized trial. Follicular lymphoma grade 3B and diffuse large B-cell lymphoma frequently show an intermediate growth pattern and/or occur simultaneously in the same tissue at the time of initial diagnosis. When occurring simultaneously follicular lymphoma grade 3B and diffuse large B-cell lymphoma do not differ significantly for genetic aberrations or phenotype but have distinct gene expression features reflecting a divergent microenvironment. Follicular lymphoma grade 3B with and without coexisting diffuse large B-cell lymphoma do not differ for major clinical parameters such as International Prognostic Index, response to immuno-chemotherapy, progression or overall survival. Follicular lymphoma grade 3B and simultaneous diffuse large B-cell lymphoma are molecularly homogenous. Histological detection of diffuse large B-cell lymphoma is not associated with features of a more aggressive disease and does not reflect transformation or progression of follicular lymphoma grade 3B.