The experimental and clinical evidence indicate that beta-2-microglobulin (beta-2m) is actively reabsorbed from the glomerular filtrate by receptors on the brush border located in the proximal third of the proximal tubule. Increased beta-2m excretion in the absence of increased filtered load of beta-2m is indicative of nephrotoxicity. The data presented show that urine beta-2m increases and creatinine concentrations decrease within four hours of administration of diatrizoate megalumine (DMG). In 9 of the 20 patients, the urinary excretion of beta-2m (U-beta-2-m) increased to clearly abnormal values. In 12 of the 20 patients beta-2m excretion expressed as mg per g creatinine (Cr), increased from normal (< 0.30) to an abnormal beta-2m excretion rate. The increased beta-2m excretion per g Cr occurring immediately after DMG administration lead us to conclude that this effect occurs when the nephrotoxic agent is present in the kidney. Based on these data we believe that the onset of abnormal urinary beta-2m excretion coincides with the presence of the causative agent. This criterion therefore, should prove to be useful in determining the time to conduct studies designed to search for the causative agent(s) in Balkan endemic nephropathy.