We investigate the white pulp compartments of 73 human spleens and demonstrate that there are several microanatomical peculiarities in man that do not occur in rats or mice. Humans lack a marginal sinus separating the marginal zone (MZ) from the follicles or the follicular mantle zone. The MZ is divided into an inner and an outer compartment by a special type of fibroblasts. An additional compartment, termed the perifollicular zone, is present between the follicular MZ and the red pulp. The perifollicular zone contains sheathed capillaries and blood-filled spaces without endothelial lining. In the perifollicular zone, in the outer MZ, and in the T cell zone fibroblasts of an unusual phenotype occur. These cells stain for the adhesion molecules MAdCAM-1, VCAM-1 (CD106), and VAP-1; the Thy-1 (CD90) molecule; smooth muscle α-actin and smooth muscle myosin; cytokeratin 18; and thrombomodulin (CD141). They are, however, negative for the peripheral node addressin, the cutaneous lymphocyte antigen, CD34, PECAM-1 (CD31), and P- and E-selectin (CD62P and CD62E). In the MZ the fibroblasts are often tightly associated with CD4-positive T lymphocytes, whereas CD8-positive cells are almost absent. Our findings lead to the hypothesis, that recirculating CD4-positive T lymphocytes enter the human splenic white pulp from the open circulation of the perifollicular zone without crossing an endothelium. Specialized fibroblasts may attract these T cells and guide them into the periarteriolar T cell area.