The occurrence and the distribution of cytokeratin (CK)-immunoreactive reticulum cells in a series of normal and pathological human lymph nodes and spleens are documented. The immunoreactive cells exhibit morphological and immunophenotypic features of so-called fibroblastic reticulum cells, with or without myoid differentiation. They invariably co-express vimentin and, to a lesser extent, desmin and muscle-specific actin isoforms. These CK-immunoreactive cells are apparently a normal subpopulation of reticulum cells, being detectable from the early stages of spleen and lymph node development. They are distributed mainly in the paracortical and medullary regions of the lymph nodes and at the periphery of the white pulp in the spleen. Their number and distribution are highly variable in different neoplastic and non-neoplastic pathological conditions but the changes are not disease specific. CK-immunoreactive reticulum cells are easily identifiable in both frozen and fixed lymphoid tissue and in cytological smears of fine-needle aspirates, provided that monoclonal antibodies whose spectrum of reactivity includes cytokeratins 8 and 18 are used. The awareness of the occurrence of CK-immunoreactive cells in normal lymphoid tissues is of particular relevance in the search for micrometastatic foci using anti-CK antibodies.