The genetic mechanisms associated with splenic marginal zone lymphoma transformation (SMZL-T) are not well defined. We studied 41 SMZL patients that eventually underwent large B-cell lymphoma transformation. Tumor material was obtained only at diagnosis (9 patients), at diagnosis and transformation (18 patients), and only at transformation (14 patients). Samples were categorized in two groups: i) at diagnosis (SMZL, n=27 samples), and ii) at transformation (SMZL-T, n=32 samples). Using copy number arrays and a next-generation sequencing custom panel, we identified that the main genomic alterations in SMZL-T involved TNFAIP3, KMT2D, TP53, ARID1A, KLF2, 1q gains and losses of 9p21.3 (CDKN2A/B) and 7q31-q32. Compared with SMZL, SMZL-T had higher genomic complexity, and higher incidence of TNFAIP3 and TP53 alterations, 9p21.3 (CDKN2A/B) losses and 6p gains. SMZL and SMZL-T clones arose by divergent evolution from a common altered precursor cell which acquired different genetic alterations in virtually all evaluable cases (12/13, 92%). Using whole genome sequencing from diagnostic and transformation samples in one patient, we observed that the SMZL-T sample carried more genomic aberrations than the diagnostic sample, identified a translocation t(14;19)(q32;q13) present in both samples, and detected a focal B2M deletion due to chromothripsis acquired at transformation. Survival analysis showed that KLF2 mutations, complex karyotype and international prognostic index at transformation predicted for a shorter survival from transformation (P=0.001, P=0.042, and P=0.007, respectively). In summary, SMZL-T are characterized by higher genomic complexity than SMZL, and characteristic genomic alterations that could represent key players in the transformation event.