Synovial tissue was obtained from medial, lateral, and suprapatellar sites of 21 knees (15 patients) with medial compartmental osteoarthritis at surgery. All patients reported pain around the medial joint of their knees while walking and climbing stairs. For investigation of the synovial innervation, six samples were stained with modified gold chloride and the others with an immunohistochemical method using antisera against neuropeptides. The extent of synovitis in each part was scored using a new 10-point scale. The results showed that the synovium had an extensive neural network in the somatic and autonomic nervous systems. Neuropeptides were most abundant, with an especially large number of substance P and calcitonin gene related peptide immunoreactive free nerve endings. Some of the substance P positive nerve endings were surrounded by monocytes. Substance P and calcitonin gene related peptide were found more frequently in the medial than in the lateral or suprapatellar areas. Substance P positive free nerve endings showed more dendritic morphologic features in the medial region than did those in the lateral and suprapatellar regions, and small nerves were accompanied by newly developed vessels in synovial villi. In the medial region, the synovitis was more remarkable than in the lateral region. These findings suggest that free nerve endings containing substance P may modulate inflammation and the pain pathway in osteoarthritis.