The molecular mechanisms involved in histologic transformation of follicular lymphoma (FL) and B-chronic lymphocytic leukemia (B-CLL) to diffuse large B-cell lymphoma (DLBCL) are heterogeneous and largely unknown. Here we explored whether aberrant somatic hypermutation, leading to the acquisition of new mutations in PIM-1, PAX-5, RhoH/TTF and c-MYC genes, is involved in transformation from FL or B-CLL to DLBCL. Eighteen sequential pairs of FL/DLBCL (n=9) and B-CLL/DLBCL (n=9) were investigated. Our findings demonstrate that acquisition of novel mutations due to aberrant somatic hypermutation was associated with DLBCL transformation in 5/9 (55.5%) cases of FL and 2/9 (22.2%) cases of B-CLL.