Although gold is one of the few therapeutic agents that has been proven effective in producing remission in patients with rheumatoid arthritis, its mechanism of action is unknown. Since nociceptive afferent and sympathetic efferent fibers of the peripheral nervous system contribute to the pathophysiology of inflammation, and since a known side effect of gold therapy is a polyneuropathy, we tested the hypothesis that gold is toxic to small-diameter peripheral nerve fibers in the rat. We found that prolonged treatment with gold, at the same dosage reported to be effective against adjuvant-induced arthritis in the rat, produced a significant decrease in the numbers of unmyelinated, but not of myelinated, axons. Gold treatment also elevated nociceptive thresholds in both articular and nonarticular structures. These results suggest that gold produces an antiinflammatory effect on arthritis by a neurotoxic effect on the peripheral nerves involved in neurogenic inflammation.