The purpose of this study is to show that the histopathological type of an orbital lymphoma can differ from the systemic follicular lymphoma that precedes it. A 44-year-old man (Patient #1) and a 50-year-old man (Patient #2) presented with generalized lymphadenopathy due to grade 1 follicular lymphoma proven on lymph node biopsy. Patient #1 was followed without treatment for 16 years when he developed a right orbital mass. Patient #2 underwent several courses of combination chemotherapy as well as radiation but relapsed. The second biopsy of the lymph node nine years later showed the same histopathological type of follicular lymphoma. He developed an orbital mass on the right side 16 years after the initial presentation. In Patient #1, excisional biopsy of the orbital masses showed extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In Patient #2, biopsy revealed the orbital mass to be T-cell/histiocyte-rich diffuse large B-cell lymphoma. In Patient #1, when comparing the original lymph node biopsy to the orbital biopsy obtained years later, no evidence for clonality was noted by polymerase chain reaction. In Patient #2, the amplification by polymerase chain reaction of the immunoglobulin heavy chain gene rearrangement in the lymph node lesion and the orbital lesion gave rise to a single discrete band with the same DNA sequence except for five nucleotide changes, indicating the same clonality in the presence of genomic changes. In conclusion, orbital lymphomas can occur as a second lymphoma with a different histopathological type in the long-term follow-up of systemic lymphomas. The original and subsequent lymphomatous lesions may or may not share neoplastic cell clonality and all genomics. [J Clin Exp Hematopathol 48(1) : 17-24, 2008]