Although circulating phagocytic cells are important mediators of glomerular injury, their recruitment mechanisms are not completely understood. In this study, the intraglomerular trafficking of leukocytes was characterized in a rat model of acute glomerular injury induced by nephrotoxic serum (NTS). Polymorphonuclear (PMN) cells infiltrated, then disappeared rapidly, reaching a peak at 2 hr. By 6 hr the PMN migration had almost reversed but small numbers persisted until Day 7. The monocyte influx began almost simultaneously but was of lesser magnitude. However, the number of ED-1+ monocytes increased progressively from 60 min to reach a plateau by Day 2 and persisted to the end of the study (Day 28). Quantitation of intraglomerular Ia+ cells suggested in situ activation of monocytes within the glomeruli. Increased Ia+ cells were first evident on Day 2. By Day 5, 80% of the intraglomerular macrophages were Ia+. Complement depletion with cobra venom factor abrogated early albuminuria, delayed the initial PMN influx, but failed to attenuate monocyte migration. T lymphocytes appeared briefly between 10 min and 2 hr. In vitro proliferation study failed to demonstrate lymphocyte sensitization to glomerular basement membrane (GBM) antigens. A unique population of cells (OX19 OX8+), possibly representing natural killer cells, was present from Day 1 to Day 14. During the secondary wave of proteinuria (autologous phase), all leukocytes had disappeared except for macrophages and a small number of OX19-, OX8+ cells. A complex intraglomerular migration of leukocytes was triggered by the binding of nephrotoxic antibodies to GBM antigens. We speculate that this cascade involves several cell-to-cell interactions necessary for the full expression of glomerular injury.