Substance P is readily detected in the synovial fluid of the knee in which it acts as a powerful inflammatory agent in response to injury and disease. It may be an objective predictor of pain after knee replacement surgery. The level of substance P was measured in the synovial fluid in both knees of 114 patients having unilateral and in 86 patients having bilateral total knee replacement for osteoarthritis. All had severe pain in the knee to be replaced and joint destruction. Substance P was elevated in 73% of replaced knees but not in normal or asymptomatic knees. Good or excellent pain relief was achieved in 97% of patients with an elevated preoperative level of substance P and in 61% of those with a normal preoperative level (p < 0.05 compared with preoperative values).