Aims:  Kaposi sarcoma herpesvirus (KSHV) is aetiologically related to Kaposi sarcoma, classical and extracavitary primary effusion lymphoma (PEL; EC‐PEL) and multicentric Castleman disease (MCD), entities preferentially occurring in HIV‐infected individuals. Characterization of HIV‐associated PELs/EC‐PELs suggests that the KSHV‐infected malignant cells originate from a pre‐terminal stage of B‐cell differentiation. However, only limited phenotypic studies have been performed on HIV+ MCD, including for PR domain containing 1 with zinc finger domain/B lymphocyte‐induced maturation protein 1 (PRDM1/BLIMP1), a key regulator of terminal B‐cell differentiation. The aim was to characterize KSHV‐infected cells in 17 cases of HIV+ MCD.Methods and results:  Double immunohistochemistry and immunohistochemistry–in situ hybridization were used to characterize the KSHV‐infected cells in MCD; the results were compared with the phenotypic profiles of 39 PELs/EC‐PELs and seven PEL cell lines. Whereas the immunophenotype of KSHV‐infected cells in MCD and malignant KSHV+ PEL cells was similar (PAX5, Bcl‐6−; PRDM1/BLIMP1, IRF4/MUM1+; Ki67+), the MCD KSHV‐infected cells differed, as they expressed OCT2, cytoplasmic λ immunoglobulin; variably expressed CD27; lacked CD138; and were Epstein–Barr virus negative.Conclusions:  Although both PEL and MCD originate from KSHV‐infected pre‐terminally differentiated B cells, these findings, with previously reported genetic studies, indicate HIV+ MCD may arise from extrafollicular B cells, whereas PELs may originate from cells that have traversed the germinal centre.