Resuscitation from major trauma or replacement of major operative blood loss frequently results in varying levels of protein depletion and alterations in plasma volume. To assess the importance of these factors on pulmonary and soft tissue transvascular fluid filtration, we compared the effects of hypoproteinemia and plasma volume expansion on the rate of lung and soft tissue transvascular fluid filtration in unanesthetized adult sheep. Ten animals were surgically prepared with chronic lung and soft tissue lymph fistulas. Lung (QL) and soft tissue (Qs) lymph flow rates were used to determine changes in transvascular fluid filtration. Initially, lactated Ringer's solution (LR) was infused to elevate pulmonary arterial wedge pressure of normoproteinemic animals (Norm/LR) 5 mm Hg for 2 1/2 hours. After a plasmapheresis-induced protein depletion of 30% to 35%, similar volume expansions with LR (Hypo/LR) and fresh frozen plasma (Hypo/Plas) were performed. Plasma, lung lymph, and soft tissue lymph oncotic pressures were determined, and transvascular oncotic gradients were calculated. Plasma volume expansion during Hypo/Plas conditions limited (p less than or equal to 0.05, 3 hours after infusion) Qs elevations compared with Hypo/LR expansion. However, there appeared to be no significant advantage with fresh frozen plasma over LR infusion in limiting QL. During fresh frozen plasma infusion, a distinct 10- to 12-hour lag in protein transport into the interstitium was observed in the soft tissue but not the lung microcirculation. The resultant differences in fluid filtration properties were in part the result of significant widening of the oncotic gradient in soft tissue. Plasma protein infusion appeared not to be beneficial over LR in limiting lung transvascular fluid filtration during hypoproteinemic states but significantly decreased soft tissue transvascular fluid flux.