Tourniquet application is a widely accepted adjuvant technique in extremity surgery. The purpose of this prospective, randomized trial was to evaluate the effect of cuff width on skeletal muscle ischemia-reperfusion injury. A 2- or 4-cm wide curved tourniquet cuff was applied around the midthigh of 36 New Zealand White rabbits and inflated to a pressure of 200 or 400 mm Hg for 2 hours: group A=2 cm to 200 mm Hg; group B=2 cm to 400 mm Hg; group C=4 cm to 200 mm Hg; group D=4 cm to 400 mm Hg. Blood levels of potassium, lactic acid, urea, lactic dehydrogenase, and creatinine phosphokinase MM isoenzyme (CPK-MM) were measured as basic indicators for limb ischemia before tourniquet inflation and 1, 5, and 30 minutes after cuff release.Potassium values did not differ among the 4 groups. Lactic acid and urea concentrations were always higher in the 400 mm Hg groups (B and D) (P<.001). However, cuff width did not affect their levels (P>.16). Lactic dehydrogenase and CPK-MM values were also greater in the 400 mm Hg groups at all times (P<.001). Further subgroup analysis of 200 mm Hg pressure groups showed higher lactic dehydrogenase (P<.02) but not CPK-MM (P>.9) concentrations in group C than in group A during the 30-minute period. At 400 mm Hg, lactic dehydrogenase and CPK-MM values were higher in group D compared with group B only 30 minutes after cuff deflation (P<.001). Broad tourniquets are associated with significantly greater and prolonged elevation of serum biochemical markers of inducible skeletal muscle ischemia-reperfusion injury compared with narrow ones. This difference is more prominent when a wide cuff is inflated to a high pressure.