The pathogenesis of acute renal failure (ARF) occurring during the course of sepsis is incompletely understood. ICAM-1 is a key cell adhesion molecule upregulated by LPS, which binds to the integrins CD11a/CD18 and CD11b/CD18 present on the surface of leukocytes. We hypothesized that ICAM-1 facilitates renal injury in LPS-induced ARF. To test this, three groups of mice (n = 8 per group) were injected i.p. with 6 mg/kg mg LPS: 1) normal C57BL/6 mice; 2) mice with a targeted deficiency of ICAM-1 (ICAM-1^-/-); and 3) mice expressing very low levels of CD18 (CD18-def). ICAM-1^-/- mice were significantly resistant to LPS-mediated ARF, as opposed to CD18-def mice, which developed severe ARF, as did wildtype controls (48h BUN 143 ± 31.5, 70.8 ± 24.4, and 185 ± 16.6 mg/dl in wildtype, ICAM-1^-/- and CD18-def mice, respectively, P < 0.05). At sacrifice, ICAM-1^-/- mice had significantly less renal neutrophil infiltration than the other two groups, as well as less histologic tubular injury. Depletion of neutrophils with mAb Gr-1 led to a profound exaggeration of TNF release and high mortality, but neutrophil-depleted mice receiving 10-fold less LPS were protected against ARF despite TNF release similar to what is normally associated with LPS-induced ARF. LPS caused a significant increase in renal expression of chemokines; however, this increase was significantly exaggerated in CD18-def mice, which may account for their lack of protection. In conclusion, these data show that ICAM-1 plays a key role in LPS-induced ARF.