The proinflammatory effects of intra-articular injection of purified phospholipase A2 from snake venom and rheumatoid synovial fluid were studied in rats. Purified soluble phospholipase A2 (PLA2) in concentrations ranging from 1000 to 20,000 units/ml, was injected intra-articularly. Histologic parameters examined were cell and protein content of synovial fluid, subsynovial cellular infiltration, synovial lining cell hyperplasia, bone erosion, and peri-articular soft tissue infiltration. Single intra-articular injections of PLA2 resulted in an acute inflammatory infiltrate of the subsynovium with maximal changes seen 2 to 6 hours after injection. Acute inflammatory changes were dose-dependent. Joints injected repeatedly at 24-hour intervals showed prominent synovial lining cell hyperplasia, maximal at 96 hours. Human synovial and snake venom PLA2s were equipotent at inducing both the acute and chronic articular changes. These changes were not seen in joints injected with inactivated PLA2. It is concluded that soluble PLA2 causes time- and dose-dependent acute inflammatory changes after a single intra-articular injection and synovial lining cell hyperplasia in response to repeated exposure to PLA2. The experimental proliferative synovitis in this model may correlate with features of acutely inflammed joints bathed in synovial fluids containing high levels of PLA2 in patients with rheumatoid arthritis.