We conducted a prospective, observational cohort study designed to compare intestinal permeability (IP) and development of multiple organ dysfunction syndrome (MODS) in a subset of critically ill patients in an intensive care unit (ICU). All patients with an expected ICU stay of 72 h or more were entered into the study, and IP was determined on a daily basis whenever possible from the urinary fractional excretion of orally administered lactulose and mannitol (LMR). Forty-seven consecutive patients were studied, and 28 developed MODS either at the time of admission or during their ICU course. These patients, as a group, had significantly worse IP at admission than did a non-MODS cohort (LnLMR: -2.10 +/- 1.10 versus -3.26 +/- 0.83). Those patients who developed MODS following admission also had a significantly greater admission IP than did the non-MODS group (-2.51 +/- 0.85). Differences in IP between cohorts could not be explained by differences in the incidence of systemic inflammatory response syndrome (SIRS)/sepsis or shock. With multivariate regression analysis, the only parameter present on admission that was predictive of subsequent MODS was IP. Differences in IP and the severity of organ dysfunction were also present (MODS severity mild: -3.01 +/- 0.72; moderate: -1.97 +/- 0.69; and severe: -1.12 +/- 0.96). Patients who developed MODS had a persistently abnormal IP during their ICU stay, and a significantly delayed improvement in their IP compared with the non-MODS cohort. We conclude that the development of MODS is associated with an abnormal and severe derangement of IP that is detectable prior to the onset of the syndrome. This observation lends credence to the premise that gastrointestinal (GI) dysfunction may be causally associated with the development of MODS in the critically ill patient.