Introduction In neonatally thymectomized mice, the intermediate cortical zones of the lymph nodes as well as the central portions of the spleen follicles (= thymus dependent areas, TDA) are depleted of lymphocytes within a few weeks (Parrott et al., 1966). The TDA's in the lymphatic tissues of mice homozygous for the gene “nude” (nu/nu) contain also a very small number of lymphocytes. Since only a few developmental stages of the lymphatic tissues in nude mice have been studied, an investigation of the postnatal differentation of their lymph nodes and spleen seemed worthwhile. Materials and Methods The mice (BALB/c) were maintained under specific pathogen-free (spf) conditions. Heterozygous (nu/+) females were mated with homozygous (nu/nu) males in order to obtain the homo- and heterozygous offsprings used in this study. Two nu/nu and two nu/+ female mice were sacrificed at the following postnatal stages: day 1, 7, 14, 21, 35, 42, 49, 63 and 84, respectively. Newborn and 7 day old mice were fixed in toto in Bouin's solution and embedded in paraffin. From the other animals, spleen and mesenteric lymph nodes were removed and processed in an identical manner. Serial sections were cut at 5 μm and stained with hematoxylin and eosin. Results The mesenteric lymph nodes of the nu/+ mice studied were indistinguishable from those of other mouse strains. In the nu/nu mouse, outer cortex and medulla of the mesenteric lymph nodes were found to develop as in normal (nu/+) animals, while the intermediate and deep cortex underwent characteristic changes. Two to three weeks after birth, a small area containing only a few lymphocytes and corresponding to the reticular connective tissue of the TDA could be seen within the intermediate cortex. In the following 3 weeks, this area was observed to have extended toward the medulla and the outer cortex. In 6–7 week-old mice, the reticular framework of the TDA, which at this stage was virtually free of lymphocytes, showed its largest extension, reaching occasionally the subcapsular sinus and the medullary cords. In adult mice (9 and 12 week-old) the reticular framework of the TDA was found to be limited to the intermediate cortex. Germinal centers were not observed in the lymph nodes of nu/nu mice. The spleen of the nu/+ mouse was found to develop as in other mouse strains. In a few splenic follicles of 6 week-old nu/nu mice, small areas consisting of a loose reticular connective tissue and containing only a few lymphocytes (= TDA) could be seen in the neighbourhood of the central artery. In later stages, the extension of these TDA's varieed considerably, as did the number of lymphocytes which were observed within them. In adult (9 and 12 week-old) nu/nu mice, only a part of the white pulp was found to form follicles, whereas the major part was irregularly dispersed among the red pulp. Discussion Three to six weeks after birth, the reticular connective tissue of the thymus-dependent areas (TDA's) in lymph nodes and spleen of nu/nu mice differentiates in spite of the fact that this area will be populated by only a few lymphocytes. It might be speculated that a small number of lymphocytes with T-cell characteristics is present in the nu/nu mouse in spite of its thymic dysgenesis. Likewise, growth of the TDA could be stimulated by hormones produced by the thymus rudiment. The differentiation of the reticular cells of the TDA could also be triggered by maternal thymic hormones crossing the placenta. Finally, the development of the reticular connective tissue of the TDA's could be completely thymus-independent.