Tissues from the urinary tract of man, the guinea-pig, mouse and rat were investigated for Ia (HLA-DR) tissue distribution with an immunohistochemical staining technique using anti-Ia monoclonal antibodies. Human and guinea-pig tissues were also investigated with a rabbit anti-human HLA-DR immunoglobulin. Ia-antigen-expressing cells were demonstrated in bladder connective tissue of man, the guinea-pig, rat and mouse. In man and the guinea-pig anti-Ia-reactive cells were present also in the bladder epithelium. In the kidney, the Ia antigens seemed to be restricted to the endothelium in man, the guinea-pig and mouse, whereas in the rat, the kidney contained anti-Ia-reactive dendritic cells in the interstitium. The staining of mouse tissues with anti-I-Ak- and anti-I-E/Ck-specific monoclonal antibodies revealed that cells of different Ia phenotypes were differently distributed in the bladder connective tissue. In sections from the mouse kidney no difference in staining was seen with the various antibodies. In experiments with mouse bone-marrow chimeras the anti-Ia-reactive cells in mouse bladder were shown to be of bone-marrow origin. In humans epithelial Ia-expressing cells could be isolated from the urine. Such cells might constitute a source of anti-Ia-reactive epithelial cells for future functional studies.