Colloid oncotic pressure (COP) and fluid shifts were studied in 43 septic (SS) patients and 33 injured (HS) patients (ISS = 48.2). During maximal postresuscitation fluid retention, plasma volume (PV/RISA), red cell volume (RBC/51Cr), inulin space (ECF), and COP were measured. Interstitial space (IFS), PV/IFS ratio, and correlation coefficients (r) were calculated. A subgroup of 22 SS patients and 22 HS patients of equal study weight were also compared. Septic patients had greater IFS expansion (17.6 L vs. 11.5 L) than HS patients who, by inference, had more intracellular expansion. Expansion of IFS in SS patients correlated (r = -0.76, p < 0.02) with reduced plasma COP; this was not seen in HS patients (r = -0.09, p > 0.35). In contrast, plasma COP correlated (r = 0.72, p < 0.001) with PV/RISA in HS patients but not in SS patients (r = 0.09, p > 0.35). We conclude: (1) SS patients with greater IFS expansion that correlates with reduced plasma COP likely have increased capillary permeability; and (2) HS patients with less IFS expansion that does not correlate with reduced plasma COP likely have maintained capillary permeability with altered IFS matrix configuration causing reduced protein exclusion.