Splenic diffuse red pulp small B-cell lymphoma is an uncommon B-cell lymphoma, now recognized as a provisional entity in the 2008 update of the WHO Classification. Additional work is required to review this entity and establish its diagnostic features. We have retrospectively analyzed the disease features in a highly selected series of 17 patients diagnosed as splenic diffuse red pulp small B-cell lymphoma. The median age was 65.5 years (range 40-79 years) and there was a predominance of males (male/female ratio: 2.4). Clinical manifestations were mainly derived from splenomegaly. Splenectomy was the front-line treatment in 11 symptomatic patients; the remaining 6 received chemotherapy initially followed by splenectomy. After a mean follow-up of 72 months, the five-year overall survival was 93%. All cases showed a purely diffuse pattern of splenic infiltration by monomorphous small cells with small round nuclei and pale cytoplasm. All bone marrow biopsies showed tumoral infiltration, with intrasinusoidal infiltration. Peripheral blood cells were small to medium-sized, with clumped chromatin and round nuclear outline and villous cytoplasm. Neoplastic cells had a CD20(+), CD23(-), bcl6(-), Annexin A1- phenotype, with frequent expression of DBA44+ (15/17) and IgG (10/15). FCM data had a B-cell phenotype (CD19(+), CD20(+), CD22(+)) with FMC7 (10/11) and CD11c (5/8) expression. Clonal IgH rearrangement studies in 4 cases showed IgVH mutations in all cases, without VH1.2 usage. Our data suggest that splenic diffuse red pulp small B-cell lymphoma is a distinct entity with morphological and immunophenotypical features that differ from those of other splenic lymphomas.