Experimental findings have demonstrated that idrocilamide exhibits antiinflammatory and muscle relaxant properties due at least in part to tissular effects. Percutaneous diffusion of a 10% glycero-alcoholic idrocilamide solution was studied in ten patients scheduled to undergo total knee replacement. Four 200-mg doses of idrocilamide were applied to the suprapatellar area at 12-hour intervals before surgery. Pain was evaluated using a visual analog scale before and after treatment. Surgery was performed 1.75 to 3.5 hours after the last idrocilamide dose. Idrocilamide was assayed using high performance liquid chromatography in tissue, plasma, and joint fluid specimens taken during the surgical procedure. Topical administration of idrocilamide on healthy skin produced significant concentrations of the drug in all the tissue specimens, including subcutaneous fat, muscle, tendon, synovium, and knee capsule. Tissue levels were consistently higher than synovial fluid and plasma levels, indicating that little systemic diffusion occurred. Idrocilamide levels in potential target tissues might influence clinical effects.