The splenomegaly, enlargement of spleen, has been observed in several diseases. It has been intended to evaluate histochemical alterations, spleen-specific enzymatic and proteomic markers during splenomegaly, and lympho-proliferative disorders from spleen of mice bearing Dalton's lymphoma. The higher expression of c-fos, c-jun, and MAPK testifies proliferation of lymphocytes. The lower expression of Pax5, higher expression of CD3, and the presence of additional form of Zap-70 suggest hypertrophy of follicles and splenomegaly influenced by weak B-cell receptor-mediated signaling, but activated T-cell receptor-mediated signaling. Simultaneously, lower levels of SOD, NDR2, and MIB2 and higher expression levels of Ataxin-7 and LDH also suggest impact of stress either as a cause or effect of cell proliferation. Spleen-specific isoform of Pax5, NDR2, MIB2, and Ataxin-7 can be considered as spleen-specific unique molecular markers for the evaluation of splenomegaly and lympho-proliferative disorders.