Lymphocyte-depleted classical Hodgkin lymphoma (LDCHL) is the rarest entity among the classical Hodgkin lymphoma (CHL) subtypes, accounting for <1% of CHL cases in Western countries. Similarly, primary splenic Hodgkin lymphoma is a rare diagnosis among all cases of lymphomatous involvement of spleen. Representing a combination of these two rare entities is the primary splenic LDCHL, with only one case reported in the literature. Here, we report second case of primary splenic LDCHL with a unique presentation. The patient was a 60-year-old Caucasian HIV-negative woman with a history of extranodal pleuropulmonary marginal zone lymphoma (MZL) treated with rituximab who presented with new-onset splenomegaly. Splenectomy revealed large number of Hodgkin/Reed–Sternberg cells (CD15+, CD30+, PAX5+ and EBER+) with the background consisting of histiocytes and smaller number of lymphocytes and eosinophils. There was no evidence of nodal or other extranodal site involvement. Thus, in addition to being a very rare entity, this case also provides an additional point of interest: the disease arose in the backdrop of previous diagnosis of extranodal pleuropulmonary MZL successfully treated with rituximab. We discuss the potential implications.