The aim of this study was to investigate serum levels, urinary excretion and in vitro peripheral blood mononuclear cell (PBMC) production of beta 2-microglobulin in patients with Balkan nephropathy and their families. Increased urinary beta 2-microglobulin excretion was found in Balkan nephropathy, chronic pyelonephritis and glomerulonephritis patients, being highest in the first group. The serum level of beta 2-microglobulin in Balkan nephropathy patients correlated with residual kidney function. Synthesis of beta 2-microglobulin by PBMC, untreated or stimulated by PHA, was not increased in Balkan nephropathy patients or their healthy family members compared to the control group of healthy persons living outside of an endemic region. This study has shown that the increased serum beta 2-microglobulin level in Balkan nephropathy patients is the consequence of the glomerular filtration rate (GFR) reduction. Urinary beta 2-microglobulin excretion was found increased not only in patients but in some healthy members of nephropathic families. beta 2-microglobulin therefore can serve as a marker of the early tubular damage in Balkan nephropathy. However, urinary beta 2-microglobulin is not specific for Balkan nephropathy, lacking specificity required for screening purposes. The different patterns of serum and urinary beta 2-microglobulin, and other urinary proteins, in patients with Balkan nephropathy from patients with chronic pyelonephritis and glomerulonephritis favor the opinion that Balkan nephropathy is a separate clinical entity.