A marked suppression of the thymusderived (T)-lymphocyte response to concanavalin A has been demonstrated in vitro during renal infection. Suppression of the T-lymphocyte response in vitro was seen as early as 2 h after the induction of renal infection, but maximum suppression was found 24-72 h later. A population of suppressor cells in the splenic lymphocyte population, generated during the host's response to infection, contributed to the depressed lymphocyte response. Removal of suppressor cells restored the mitogenic responsiveness of the remaining splenic lymphocytes. Conversely, in co-culture experiments, a suppressor cell present in the splenic lymphocyte population of pyelonephritic animals was shown to be capable of suppressing the mitogenic responsiveness of normal splenic lymphocytes. Significantly reduced host vs. graft responses by the pyelonephritic animals confirmed, in vivo, the depression of cell-mediated immune mechanisms.An additional suppressive factor was found in the serum of pyelonephritic animals which depressed in vitro the mitogenic responsiveness of splenic lymphocytes from normal animals. Support for the suppressive role of this serum factor was found when splenic lymphocytes from pyelonephritic animals were tested in vivo in the absence of homolgous serum (graft vs. host). Under these conditions, the lymphocytes showed an enhanced reaction compared with lymphocytes from normal animals. The presence of a suppressor cell population and a serum factor, both capable of depressing cell-mediated mechanisms, may be major factors contributing to the establishment of infection in the kidney.