Splenic marginal zone lymphoma (SMZL) is a recently described and distinctive type of splenic lymphoma and is characterized by an indolent clinical course. By analyzing a large series of SMZL cases, we recognized the existence of a subset of 6 cases characterized by an aggressive clinical course that led to death caused by the tumor in 5 of 6 cases, whereas the remaining patient showed signs of tumor progression. The morphological, immunohistological, and molecular study of these cases has allowed us to detect precise distinctive features of this SMZL variant. The cases included here were characterized by massive splenomegaly and a morphological picture showing a micronodular pattern of splenic involvement with follicle replacement, biphasic cytology, and marginal zone differentiation. Unlike classical SMZL cases, a conspicuous component of larger lymphocytes was distributed in the marginal zone ring, occasionally overrunning it, with isolated presence of the same cells within the central small cell component and also in the red pulp. The bone marrow and peripheral lymph nodes showed similar histological findings to those described for SMZL in these locations. The genetic and molecular study of these cases showed no alterations specific to other lymphoma types, such as t14;18 and t11;14. Instead of this, it showed 7q loss in 3 of 5 cases, p53 inactivation in 2 of 6 cases, cyclinD1 overexpression in 2 of 6 cases, and the presence of translocations involving the 1q32 region in 2 of 4 cases. The recognition of this aggressive variant, besides offering a prognostic indication, could lead to a more suitable form of clinical management of these patients. Further molecular studies would clarify the role of the different genetic alterations found.