Whether the arterial tourniquet in total knee arthroplasty (TKA) is a friend or a foe is still debated. Longer ischemia causes hypoxic damage; yet short duration of a tourniquet may influence outcome. Understanding the time-dependent influence of the tourniquet in TKA patients could improve the overall outcome and safety. The purpose of the study was to measure the tourniquet-induced time-dependent alterations in skeletal muscle metabolism in TKA to establish a 'safe tourniquet time.'In the femoral quadriceps muscle of 12 patients undergoing a total knee arthroplasty with a tourniquet (TKA) we measured the ischemic response using microdialysis. Lactate, pyruvate, glucose and glycerol were measured in the muscle underneath the tourniquet, in the ischemic muscle distally to the tourniquet and in the opposite muscle as a reference.Lactate pyruvate ratio (L/P ratio) increased time-dependently after 15min of ischemia. L/P ratio increased faster underneath the tourniquet compared to ischemic tissue distal to the tourniquet. Glycerol was elevated underneath the tourniquet compared to ischemic tissue distal to the tourniquet and correlated to the individual ischemic response. Only minor increases in creatine-kinase, asparagine-aminotransferase, and lactate-dehydrogenase were observed. Thirty minutes of reperfusion normalized lactate levels.The muscle underneath the tourniquet suffered more from ischemia than the ischemic tissue distal to the tourniquet. Less than 15min of ischemia did not increase ischemic markers. If any muscle damage occurs from longer tourniquet time, it is likely reversible and occurs mainly underneath the tourniquet. Fifteen minutes of ischemia appears safe.