The effect of 24 h caval/iliac venous obstruction on interstitial fluid volume (IFV), hydrostatic (Pi) and colloid osmotic (COPi) pressure in hindlimb skeletal muscle was studied in three groups of rats: Group I (G I), Intact innervation, unrestricted motor activity. Group II (G II), Sympathectomized, unrestricted. Group III (G III), Motoric and sympathetic denervation + immobilization of the hindlimbs. Subcutaneous edema was present in all groups at femoral venous pressure (Pv) exceeding 13 mmHg. Skeletal muscle edema was seen in G III at Pv above 12 mmHg, in two rats in G II at Pv of 18 and 23 mmHg, but in no rats in GI. Without venous obstruction, control COPi was 8-10 mmHg in all groups. With increasing Pv, COP fell moderately in G I and G II: delta COPi/delta Pv = 0.22. In G III, COPi fell from a control of 8.2 to 3.5 mmHg at a Pv of 12 mmHg (delta COPi/delta Pv = 0.52), but remained constant with further rise in Pv. Pi was about 0 mmHg in controls and 1-2 mmHg in rats with muscle edema. IFV rose by 6% per mmHg increase in Pv in G III, and 2% in G I and G II. This expansion of IFV may explain about 70% of the fall in COPi, the remaining being due to lymphatic washout of interstitial proteins. It is concluded that normal muscle activity together with dilution and washout of interstitial proteins constitute the main edema preventing mechanisms in skeletal muscle.