PURPOSE. A marked cellular infiltrate has been observed when endotoxin (lipopolysaccharide [LPS]) is injected into the mouse eye, but systemically injected LPS does not produce a comparable effect. Several hypotheses were tested to reconcile this discordance. METHODS. BALB/c mice were injected intravitreally (ivt) or intraperitoneally (ip) with Escherichia coli LPS. Uveitis was assessed by traditional and intravital microscopy. Cytokine levels in the eye, plasma, or spleen were measured by single or multiplex ELISA assays. RESULTS. The eye's higher sensitivity was confirmed to local LPS exposure, as 250 ng ivt LPS produced a brisk leukocytic infiltrate whereas ip injection of 100 μg LPS did not. The hypothesis was tested that the lack of a cellular infiltrate after ip LPS is explained by less induction of cytokines in the eye, but surprisingly, ip LPS resulted in comparable cytokine levels to ivt LPS. The hypothesis was disproved that the eye's sensitivity to local LPS is due to lack of expression of intracellular inhibitors of LPS such as A20, IRAK-M, or SARM. Finally, the hypothesis that systemic LPS inhibits diapedesis was tested by injection of LPS ip and ivt simultaneously, a strategy that did not significantly reduce leukocyte rolling or sticking in iris vessels but blocked the cellular infiltrate normally seen with ivt LPS. CONCLUSIONS. Systemic and local LPS exposures produce discordant effects within the murine eye. The hypothesis that systemic LPS desensitizes leukocytes to the stimuli responsible for transmigration offers a plausible explanation for this discordance.